Cyclic amine derivatives-CCR-3 receptor antagonists

ABSTRACT

This invention relates to certain cyclic amine derivatives of Formula (I) 
                 
 
that are CCR-3 receptor antagonists, pharmaceutical compositions containing them, methods for their use and methods for preparing these compounds.

CROSS-REFERENCE TO RELATED APPLICATIONS

This Application is a divisional of U.S. patent application Ser. No.09/965,068 filed on Sep. 26, 2001, now U.S. Pat. No. 6,683,074 which isa divisional of U.S. patent application Ser. No. 09/134,013 filed onAug. 14, 1998 now U.S. Pat. No. 6,323,223. This application claims thebenefit under Title 35 U.S.C. 119(e) of U.S. Provisional Application No.60/056,001 filed Aug. 18, 1997. The disclosures of the aforementionedapplications are incorporated herein by reference in their entirety.

FIELD OF THE INVENTION

This invention relates to certain cyclic amine derivatives that areCCR-3 receptor antagonists, pharmaceutical compositions containing them,methods for their use and, methods for preparing these compounds.

BACKGROUND INFORMATION

Tissue eosinophilia is a feature of a number of pathological conditionssuch as asthma, rhinitis, eczema, inflammatory bowel diseases andparasitic infections ((see Bousquet, J. et al. N. Eng. J. Med. 323:1033-1039 (1990) and Kay, A. B. and Corrigan. C. J. Br. Med. Bull.48:51-64 (1992)). In asthma, eosinophil accumulation and activation areassociated with damage to bronchial epithelium and hyperresponsivenessto constrictor mediators. It is established that chemokines such asRANTES, eotaxin, MCP-2, MCP-3 and MCP-4 activate eosinophils ((seeBaggiolini, M. and Dahinden, C. A. Immunol. Today. 15:127-133 (1994),Rot, A. M. et al. J. Exp. Med. 176, 1489-1495 (1992) and Ponath. P. D.et al. J. Clin. Invest., Vol. 97, #3, 604-612 (1996)). However, unlikeRANTES and MCP-3 which also induce the migration of other leukocyte celltypes, eotaxin is selectively chemotactic for eosinophils ((seeGriffith-Johnson, D. A et al. Biochem. Biophy. Res. Commun. 197:1167(1993) and Jose, P. J. et al. Biochem. Biophy. Res. Commun. 207, 788(1994)). Specific eosinophil accumulation was observed at the site ofadministration of eotaxin whether by intradermal or intraperitonealinjection or aerosol inhalation ((see Griffith-Johnson, D. A et al.Biochem. Biophy. Res. Commun. 197:1167 (1993); Jose, P. J. et al. J.Exp. Med. 179, 881-887 (1994); Rothenberg, M. E. et al. J. Exp. Med.181, 1211 (1995) and Ponath. P. D. J. Clin. Invest., Vol. 97, #3,604-612 (1996)).

The CCR-3 receptor has been identified as a major chemokine receptorwhich eosinophils use for their response to eotaxin, RANTES and MCP-3.It is expressed predominantly on the surface of eosinophils and ishighly selective for eotaxin. When transfected into a murine pre-βlymphoma line, the CCR-3 receptor bound eotaxin, RANTES and MCP-3 andconferred chemotactic responses on these cells to these chemokines ((seePonath. P. D. et al. J. Exp. Med. 183, 2437-2448 (1996)).

Recently, studies have shown that pretreatment of eosinophils with ananti-CCR-3 mAb completely inhibits eosinophil chemotaxis to eotaxin,RANTES and MCP-3 ((see Heath H. et al. J. Clin. Invest., Vol. 99, #2,178-184 (1997)) indicating that CCR-3 antagonists are useful for thetreatment of eosinophil-mediated inflammatory diseases.

Glucocorticoids such as dexamethasone, methprednisolone andhydrocortisone have been used for treating many eosinophil-relateddisorders, including bronchial asthma ((R. P. Schleimer et. al., Am.Rev. Respir. Dis., 141, 559 (1990)). The glucocorticoids are believed toinhibit IL-5, IL-3 mediated eosinophil survival in these diseases.However, prolonged use of glucocorticoids can lead to side effects suchas glaucoma, osteoporosis and growth retardation in the patients ((seeHanania N. A et al., J. Allergy and Clin. Immunol., Vol. 96, 571-579(1995) and Saha M. T. et al, Acta Paediatrica, Vol. 86, #2, 138-142(1997)). It is therefore desirable to have an alternative means oftreating eosinophil related diseases without incurring these undesirableside effects.

The present invention provides a means of combating eosinophil induceddiseases, such as asthma.

SUMMARY OF THE INVENTION

In a first aspect, this invention provides compounds selected from thegroup of compounds represented by Formula (I):

wherein:

-   -   T and U are both nitrogen; or one of T and U is nitrogen and the        other is carbon;    -   R¹ and R² are, independently of each other, hydrogen or alkyl;    -   n is an integer from 0 to 2, provided that when n is 0, either T        or U is carbon;    -   m is an integer from 0 to 3;    -   Ar and Ar¹ are, independently of each other, aryl or heteroaryl;    -   F is alkylene, alkenylene or a bond, provided that when T and U        are nitrogen and F is alkylene, then R⁴ is not aryl.    -   Each R is independently hydrogen or alkyl, or R together with        either R³ or R⁴ and the atoms to which they are attached form a        carbocycle or a heterocycle;    -   R³ and R⁴ are, independently of each other, selected from:        -   (i) hydrogen, alkyl, alkenyl, haloalkyl, cycloalkyl,            cycloalkylalkyl, heteroaryl, heteroaralkyl, heterocyclyl,            heterocyclylalkyl, heteroalkyl, cyano or -(alkylene)-C(O)—Z            where Z is alkyl, haloalkyl, alkoxy, haloalkyloxy, hydroxy,            amino, mono- or disubstituted amino, aryl, aralkyl, aryloxy,            aralkyloxy, heteroaryl, heteroaryloxy or heteroaralkyloxy,            provided that both R³ and R⁴ are not hydrogen; or        -   (ii) R³ and R⁴ together with the carbon atom to which they            are attached form a carbocycle or a heterocycle;    -   E is —C(O)N(R⁵)—, —SO₂N(R⁵)—, —N(R⁶)C(O)N(R⁵)—, —N(R⁶)SO₂N(R⁵)—,        —N(R⁶)C(S)N(R⁵)—, —N(R⁶)C(O)—, —N(R⁶)C(O)O—, —OC(O)N(R⁶)— or        —N(R⁶)SO₂— wherein:        -   R⁵ is:        -   (i) hydrogen, alkyl, acyl, haloalkyl, cycloalkyl,            cycloalkylalkyl, aryl, aralkyl, aralkenyl, heteroaryl,            heteroaralkyl, heterocyclylalkyl, heteroalkyl, or            -(alkylene)-C(O)—Z where Z is alkyl, haloalkyl, alkoxy,            haloalkyloxy, hydroxy, amino, mono- or disubstituted amino,            aryl, aralkyl, aryloxy, aralkyloxy, heteroaryl,            heteroaryloxy or heteroaralkyloxy; or        -   (ii) R⁵ together with either R³ or R⁴ and the atoms to which            they are attached forms a heterocycloamino group; and        -   R⁶ is hydrogen, alkyl, acyl, haloalkyl, cycloalkyl,            cycloalkylalkyl, aryl, aralkyl, aralkenyl, heteroaryl,            heteroaralkyl, heterocyclylalkyl, heteroalkyl, or            -(alkylene)-C(O)—Z where Z is alkyl, haloalkyl, alkoxy,            haloalkyloxy, hydroxy, amino, mono- or disubstituted amino,            aryl, aralkyl, aryloxy, aralkyloxy, heteroaryl,            heteroaryloxy or heteroaralkyloxy,    -   provided that when T is nitrogen and E is —C(O)N(R⁵)—,        —SO₂N(R⁵)—, —N(R⁶)C(O)N(R⁵)—, —N(R⁶)SO₂N(R⁵)— or        —N(R⁶)C(S)N(R⁵)—, then m>0;    -   Q is —R⁷—W—R⁸— wherein:        -   R⁷ is an alkylene chain of between 1-6 carbon atoms            inclusive;        -   R⁸ is a bond or an alkylene chain of between 0-4 carbon            atoms inclusive;        -   W is a bond or a group selected from —C(O)—, —NR⁹—, —O—,            —S(O)₀₋₂—, —C(O)N(R⁹)—, —N(R⁹)C(O)—, —N(R⁹)SO₂—, —SO₂N(R⁹)—,            —N(R⁹)C(O)N(R⁹)—, —N(R⁹)SO₂N(R⁹)— or —N(R⁹)C(S)N(R⁹)—            wherein:            -   R⁹ is hydrogen, alkyl, acyl, haloalkyl, cycloalkyl,                cycloalkylalkyl, aryl, aralkyl, aralkenyl, heteroaryl,                heteroaralkyl, heterocycloalkyl, heteroalkyl, or                -(alkylene)-C(O)—Z where Z is alkyl, haloalkyl, alkoxy,                haloalkyloxy, hydroxy, amino, mono- or disubstituted                amino, aryl, aralkyl, aryloxy, aralkyloxy, heteroaryl,                heteroaryloxy or heteroaralkyloxy,    -   provided that when T is nitrogen and U is carbon then W is not        —C(O)N(R⁹)—, and prodrugs, individual isomers, mixtures of        isomers and pharmaceutically acceptable salts thereof.

In a second aspect, this invention provides pharmaceutical compositionscontaining a therapeutically effective amount of a compound of Formula(I) or its pharmaceutically acceptable salt and a pharmaceuticallyacceptable excipient.

In a third aspect, this invention provides a method of treatment of adisease in a mammal treatable by administration of a CCR-3 receptorantagonist, comprising administration of a therapeutically effectiveamount of a compound of Formula (I) or its pharmaceutically acceptablesalt. The disease states include respiratory diseases such as asthma.

DETAILED DESCRIPTION OF THE INVENTION Definitions

Unless otherwise stated, the following terms used in the specificationand claims have the meanings given below:

“Alkyl” means a linear saturated monovalent hydrocarbon radical of oneto six carbon atoms or a branched saturated monovalent hydrocarbonradical of three to six carbon atoms, e.g., methyl, ethyl, propyl,2-propyl, pentyl, and the like.

“Alkenyl” means a linear monovalent hydrocarbon radical of two to sixcarbon atoms or a branched monovalent hydrocarbon radical of three tosix carbon atoms, containing at least one double bond, e.g., ethenyl,propenyl, and the like.

“Alkylene” means a linear saturated divalent hydrocarbon radical of oneto six carbon atoms or a branched saturated divalent hydrocarbon radicalof three to six carbon atoms, e.g., methylene, ethylene, propylene,2-methylpropylene, pentylene, and the like.

“Alkenylene” means a linear divalent hydrocarbon radical of two to sixcarbon atoms or a branched divalent hydrocarbon radical of three to sixcarbon atoms, containing at least one double bond, e.g., ethenylene,2,4-pentadienylene, and the like.

“Acyl” means a radical —C(O)R where R is hydrogen, alkyl, alkenyl,cycloalkyl, heteroalkyl, haloalkyl, aryl, aralkyl, heteroaralkyl orheteroaryl, e.g., acetyl, benzoyl, thenoyl, and the like.

“Acyloxy” means a radical —OC(O)R where R is hydrogen, alkyl, alkenyl,cycloalkyl, heteroalkyl, haloalkyl or optionally substituted phenyl,e.g., acetoxy, benzoyloxy, and the like.

“Acylamino” means a radical —NRC(O)R′ where R is hydrogen or alkyl andR′ is hydrogen, alkyl, alkenyl, cycloalkyl, heteroalkyl, haloalkyl oroptionally substituted phenyl, e.g., acetylamino, trifluoroacetylamino,benzoylamino, methylacetylamino, and the like.

“Halo” means fluoro, chloro, bromo or iodo, preferably fluoro andchloro.

“Haloalkyl” means alkyl substituted with one or more same or differenthalo atoms, e.g., —CH₂Cl, —CF₃, —CH₂CF₃, —CH₂CCl₃, and the like.

“Cycloalkyl” means a saturated monovalent cyclic hydrocarbon radical ofthree to six ring carbons, e.g., cyclopropyl, cyclohexyl, and the like.

“Carbocycle” means a saturated, cyclic group of 3 to 6 ring atoms inwhich all the ring atoms are carbon, e.g., cyclopentyl, cyclohexyl, andthe like.

“Monosubstituted-amino” means a radical —NHR where R is alkyl,heteroalkyl, haloalkyl, cycloalkyl, cycloalkylalkyl or optionallysubstituted phenyl, e.g., methylamino, (1-methylethyl)amino,phenylamino, and the like.

“Disubstituted-amino” means a radical —NRR′ where R and R′ areindependently alkyl, alkenyl, heteroalkyl, haloalkyl, cycloalkyl,cycloalkylalkyl or optionally substituted phenyl. Representativeexamples include, but are not limited to, dimethylamino,methylethylamino, di(1-methylethyl)amino, methylbenzylamino, and thelike.

“Aryl” means a monovalent monocyclic or bicyclic aromatic hydrocarbonradical of 6 to 10 ring atoms, and optionally substituted independentlywith one or more substituents, preferably one, two or three substituentsselected from alkyl, haloalkyl, heteroalkyl, cycloalkyl,cycloalkylalkyl, halo, cyano, nitro, acyloxy, alkoxy, optionallysubstituted phenyl, heteroaryl, heteroaralkyl, amino, monosubstitutedamino, disubstituted amino, acylamino, hydroxylamino, amidino,guanidino, cyanoguanidinyl, hydrazino, hydrazido, —OR [where R ishydrogen, alkyl, haloalkyl, alkenyl, cycloalkyl, cycloalkylalkyl,optionally substituted phenyl, heteroaryl or heteroaralkyl], —S(O)_(n)R[where n is an integer from 0 to 2 and R is hydrogen, alkyl, haloalkyl,alkenyl, cycloalkyl, cycloalkylalkyl, optionally substituted phenyl,heteroaryl, heteroaralkyl, amino, mono or disubstituted amino], —NRSO₂R′(where R is hydrogen or alkyl and R′ is alkyl, amino, monosubstituted ordisubstituted amino) —C(O)R (where R is hydrogen, alkyl, alkenyl,cycloalkyl, heteroalkyl, haloalkyl or optionally substituted phenyl),—COOR (where R is hydrogen, alkyl, optionally substituted phenyl,heteroaryl or heteroaralkyl), —(alkylene)COOR (where R is hydrogen,alkyl, optionally substituted phenyl, heteroaryl or heteroaralkyl),methylenedioxy, 1,2-ethylenedioxy, —CONR′R″ or -(alkylene)CONR′R″ (whereR′ and R″ are independently selected from hydrogen, alkyl, cycloalkyl,haloalkyl, cycloalkylalkyl, optionally substituted phenyl, heteroaryland heteroaralkyl). More specifically the term aryl includes, but is notlimited to, phenyl, 1-naphthyl, 2-naphthyl, and derivatives thereof.

“Optionally substituted phenyl” means a phenyl group which is optionallysubstituted independently with one, two or three substituents selectedfrom alkyl, haloalkyl, halo, nitro, cyano, —OR (where R is hydrogen oralkyl), —NRR′ (where R and R′ are independently of each other hydrogenor alkyl), —COOR (where R is hydrogen or alkyl) or —CONR′R″ (where R′and R″ are independently selected from hydrogen or alkyl). “Heteroaryl”means a monovalent monocyclic or bicyclic aromatic radical of 5 to 10ring atoms containing one, two, or three ring heteroatoms selected fromN, O, or S, the remaining ring atoms being C. The aromatic radical isoptionally substituted independently with one or more substituents,preferably one or two substituents selected from alkyl, haloalkyl,heteroalkyl, cycloalkyl, cycloalkylalkyl, halo, cyano, nitro, acyloxy,optionally substituted phenyl, amino, monosubstituted amino,disubstituted amino, acylamino, hydroxyamino, amidino, guanidino,cyanoguanidinyl, hydrazino, hydrazido, —OR [where R is hydrogen, alkyl,haloalkyl, alkenyl, cycloalkyl, cycloalkylalkyl or optionallysubstituted phenyl], —S(O)_(n)R [where n is an integer from 0 to 2 and Ris hydrogen, alkyl, haloalkyl, alkenyl, cycloalkyl, cycloalkylalkyl,optionally substituted phenyl, amino, mono or disubstituted amino],—C(O)R (where R is hydrogen, alkyl, alkenyl, cycloalkyl, heteroalkyl,haloalkyl or optionally substituted phenyl), —COOR (where R is hydrogen,alkyl, or optionally substituted phenyl), -(alkylene)COOR (where R ishydrogen, alkyl or optionally substituted phenyl), methylenedioxy,1,2-ethylenedioxy, —CONR′R″ or -(alkylene)CONR′R″ (where R′ and R″ areindependently selected from hydrogen, alkyl, cycloalkyl, haloalkyl,cycloalkylalkyl or optionally substituted phenyl). More specifically theterm heteroaryl includes, but is not limited to pyridyl, pyrrolyl,thiophene, pyrazolyl, thiazolyl, imidazolyl, pyrimidinyl, thiadiazolyl,indolyl, carbazolyl, azaindolyl, benzofuranyl, benzotriazolyl,benzisoxazolyl, purinyl, quinolinyl, benzopyranyl, and derivativesthereof.

“Heterocycloamino” means a saturated or unsaturated monovalent cyclicgroup of 5 to 8 ring atoms, wherein at least one ring atom is N andoptionally contains a second ring heteroatom selected from the groupconsisting of N, O, or S(O)_(n) (where n is an integer from 0 to 2), theremaining ring atoms being C. The heterocycloamino ring may be fused toa heteroaryl ring, or it may be optionally substituted independentlywith one or more substituents, preferably one or two substituents,selected from alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl,aralkyl, heteroaryl, heteroaralkyl, halo, cyano, acyl, amino,monosubstituted amino, disubstituted amino, —COOR (where R is hydrogenor alkyl), —XR (where X is O or S(O)_(n), n is an integer from 0 to 2,and R is hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl,aralkyl, heteroaryl or heteroaralkyl) or —CONR′R″ (where R′ and R″ areindependently selected from hydrogen or alkyl). Representative examplesinclude but are not limited to pyrrolidino, piperidino,4-benzoylpiperidino, morpholino, piperazino,4-(4-benzyloxyphenyl)piperazino, indolino, and the like.

“Heterocycle” or “Heterocyclyl” means a saturated or unsaturated cyclicradical of 3 to 8 ring atoms in which one or two ring atoms areheteroatoms selected from N, O, or S(O)_(n) (where n is an integer from0 to 2). The heterocyclo ring may be optionally substitutedindependently with one, two or three substituents selected from alkyl,haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl,heteroaralkyl, halo, cyano, acyl, acylamino, amino, monosubstitutedamino, disubstituted amino, —COOR (where R is hydrogen or alkyl), —XR(where X is O or S(O)_(n), where n is an integer from 0 to 2 and R ishydrogen, alkyl, haloalkyl, cycloalkyl, aralkyl, aryl, heteroaryl orheteroaralkyl) or —CONR′R″ (where R′ and R″ are independently selectedfrom hydrogen or alkyl). Representative examples include, but are notlimited to tetrahydropyranyl, piperidino, 1-(4-chlorophenyl)piperidino,and the like.

“Heteroalkyl” means an alkyl, cycloalkyl, or cycloalkylalkyl radical asdefined ; above, carrying a substituent containing a heteroatom selectedfrom N, O, S(O)_(n) where n is an integer from 0 to 2. Representativesubstituents include —NR^(a)R^(b), —OR^(a) or —S(O)_(n)R^(c), wherein nis an integer from 0 to 2, R^(a) is hydrogen, alkyl, haloalkyl,cycloalkyl, cycloalkylalkyl, optionally substituted phenyl, pyridyl, or—COR (where R is alkyl), R^(b) is hydrogen, alkyl, —SO₂R (where R isalkyl or hydroxyalkyl), —SO₂NRR′ (where R and R′ are independently ofeach other hydrogen or alkyl), —CONR′R″, (where R′ and R″ areindependently selected from hydrogen or alkyl) and R^(c) is hydrogen,alkyl, cycloalkyl, cycloalkylalkyl, optionally substituted phenyl,amino, monosubstituted amino, or disubstituted amino. Representativeexamples include, but are not limited to 2-methoxyethyl,benzyloxymethyl, thiophen-2-ylthiomethyl, and the like.

“Hydroxyalkyl” means a linear monovalent hydrocarbon radical of two tosix carbon atoms or a branched monovalent hydrocarbon radical of threeor six carbons substituted with one or two hydroxy groups, provided thatif two hydroxy groups are present they are not both on the same carbonatom. Representative examples include, but are not limited to,2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl,1-(hydroxymethyl)-2-methylpropyl, 2-hydroxybutyl, 3hydroxybutyl,4hydroxybutyl, 2,3-dihydroxypropyl, 1-(hydroxymethyl)-2-hydroxyethyl,2,3-dihydroxybutyl, 3,4-dihydroxybutyl and2-(hydroxymethyl)-3-hydroxypropyl, preferably 2-hydroxyethyl,2,3-dihydroxypropyl, and 1-(hydroxymethyl)-2-hydroxyethyl.

“Cycloalkylalkyl” means a radical —R^(a)R^(b) where R^(a) is an alkylenegroup and R^(b) is a cycloalkyl group as defined above e.g.,cyclopropylmethyl, cyclohexylpropyl, 3-cyclohexyl-2-methylpropyl, andthe like.

“Aralkyl” means a radical —R^(a)R^(b) where R^(a) is an alkylene groupand R^(b) is an aryl group as defined above e.g., benzyl, phenylethyl,3-(3-chlorophenyl)-2-methylpentyl, and the like.

“Heteroaralkyl” means a radical —R^(a)R^(b) where R^(a) is an alkylenegroup and R^(b) is a heteroaryl group as defined above e.g.,pyridin-3-ylmethyl, 3-(benzofuran-2-yl)propyl, and the like.

“Heterocyclylalkyl” means a radical —R^(a)R^(b) where R^(a) is analkylene group and R^(b) is a heterocyclyl group as defined above e.g.,tetrahydropyran-2-ylmethyl, 4-methylpiperazin-1-ylethyl, and the like.

“Alkoxy”, “haloalkyloxy”, “aryloxy”, “heteroaryloxy”, “aralkyloxy”, or“heteroaralkyloxy” means a radical —OR where R is an alkyl, haloalkyl,aryl, heteroaryl, aralkyl, or heteroaralkyl respectively as definedabove e.g., methoxy, phenoxy, pyridin-2-yloxy, benzyloxy, and the like.

“Optional” or “optionally” means that the subsequently described eventor circumstance may but need not occur, and that the descriptionincludes instances where the event or circumstance occurs and instancesin which it does not. For example, “heterocyclo group optionally mono-or di- substituted with an alkyl group” means that the alkyl may butneed not be present, and the description includes situations where theheterocyclo group is mono- or disubstituted with an alkyl group andsituations where the heterocyclo group is not substituted with the alkylgroup.

“Amino-protecting group” refers to those organic groups intended toprotect nitrogen atoms against undesirable reactions during syntheticprocedures e.g., benzyl, benzyloxycarbonyl (CBZ), t-butoxycarbonyl(BOC), trifluoroacetyl, and the like.

Compounds that have the same molecular formula but differ in the natureor sequence of bonding of their atoms or the arrangement of their atomsin space are termed “isomers”. Isomers that differ in the arrangement oftheir atoms in space are termed “stereoisomers”. Stereoisomers that arenot mirror images of one another are termed “diastereomers” and thosethat are non-superimposable mirror images of each other are termed“enantiomers”. When a compound has an asymmetric center, for example, itis bonded to four different groups, a pair of enantiomers is possible.An enantiomer can be characterized by the absolute configuration of itsasymmetric center and is described by the R- and S-sequencing rules ofCahn and Prelog, or by the manner in which the molecule rotates theplane of polarized light and designated as dextrorotatory orlevorotatory (i.e., as (+) or (−)-isomers respectively). A chiralcompound can exist as either individual enantiomer or as a mixturethereof. A mixture containing equal proportions of the enantiomers iscalled a “racemic mixture”.

The compounds of this invention may possess one or more asymmetriccenters; such compounds can therefore be produced as individual (R)- or(S)- stereoisomers or as mixtures thereof. For example, if the R³ and R⁴substituents in a compound of Formula (I) are different, then the carbonto which they are attached is an asymmetric center and the compound ofFormula (I) can exist as an (R)- or (S)-stereoisomer. Unless indicatedotherwise, the description or naming of a particular compound in thespecification and claims is intended to include both individualenantiomers and mixtures, racemic or otherwise, thereof. The methods forthe determination of stereochemistry and the separation of stereoisomersare well-known in the art (see discussion in Chapter 4 of “AdvancedOrganic Chemistry”, 4th edition J. March, John Wiley and Sons, New York,1992).

A “pharmaceutically acceptable excipient” means an excipient that isuseful in preparing a pharmaceutical composition that is generally safe,non-toxic and neither biologically nor otherwise undesirable, andincludes an excipient that is acceptable for veterinary use as well ashuman pharmaceutical use. “A pharmaceutically acceptable excipient” asused in the specification and claims includes both one and more than onesuch excipient.

A “pharmaceutically acceptable salt” of a compound means a salt that ispharmaceutically acceptable and that possesses the desiredpharmacological activity of the parent compound. Such salts include:

(1) acid addition salts, formed with inorganic acids such ashydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,phosphoric acid, and the like; or formed with organic acids such asacetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid,glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid,malic acid, maleic acid, fumaric acid, tartaric acid, citric acid,benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelicacid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonicacid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid,4-chlorobenzenesulfonic acid, 2-napthalenesulfonic acid,4-toluenesulfonic acid, camphorsulfonic acid,4-methylbicyclo[2.2.2]oct-2-ene-1-carboxylic acid, glucoheptonic acid,4,4′-methylenebis- (3-hydroxy-2-ene-1-carboxylic acid),3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid,lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynapthoicacid, salicylic acid, stearic acid, muconic acid, and the like; or

(2) salts formed when an acidic proton present in the parent compoundeither is replaced by a metal ion, e.g., an alkali metal ion, analkaline earth ion, or an aluminum ion; or coordinates with an organicbase such as ethanolamine, diethanolamine, triethanolamine,tromethamine, N-methylglucamine, and the like.

“Leaving group” has the meaning conventionally associated with it insynthetic organic chemistry i.e., an atom or group capable of beingdisplaced by a nucleophile and includes halogen, alkanesulfonyloxy,arenesulfonyloxy, ester, or amino such as chloro, bromo, iodo, mesyloxy,tosyloxy, trifluorosulfonyloxy, methoxy, N,O-dimethylhydroxylamino, andthe like.

“Pro-drugs” means any compound which releases an active parent drugaccording to Formula (I) in vivo when such prodrug is administered to amammalian subject. Prodrugs of a compound of Formula (I) are prepared bymodifying functional groups present in the compound of Formula (I) insuch a way that the modifications may be cleaved in vivo to release theparent compound. Prodrugs include compounds of Formula (I) wherein ahydroxy, sulfhydryl or amino group in compound (I) is bonded to anygroup that may be cleaved in vivo to regenerate the free hydroxyl,amino, or sulfhydryl group, respectively. Examples of prodrugs include,but are not limited to esters (e.g., acetate, formate, and benzoatederivatives), carbamates (e.g., N,N-dimethylaminocarbonyl) of hydroxyfunctional groups in compounds of Formula (I), and the like.

“Treating” or “treatment” of a disease includes:

(1) preventing the disease, i.e. causing the clinical symptoms of thedisease not to develop in a mammal that may be exposed to or predisposedto the disease but does not yet experience or display symptoms of thedisease,

(2) inhibiting the disease, i.e., arresting or reducing the developmentof the disease or its clinical symptoms, or

(3) relieving the disease, i.e., causing regression of the disease orits clinical symptoms.

A “therapeutically effective amount” means the amount of a compoundthat, when administered to a mammal for treating a disease, issufficient to effect such treatment for the disease. The“therapeutically effective amount” will vary depending on the compound,the disease and its severity and the age, weight, etc., of the mammal tobe treated.

Nomenclature

The nomenclature used in this application is generally based on theIUPAC recommendations, e.g.,

a compound of Formula (I) where T and U are nitrogen, n and m are 1, R,R¹, R² and R³ are hydrogen, R⁴ is 1-methylethyl, E is —C(O)NH—, F is abond, Q is —CH₂—, Ar is phenyl, Ar¹ is 3,4-chlorophenyl and thestereochemistry at the carbon to which R³ and R⁴ are attached is RS isnamed,N-{1(RS)-[4-(3,4-dichlorobenzyl)piperazin-1-ylmethyl]-2-methylpropyl}benzamide.

a compound of Formula (I) where T and U are nitrogen, n and m are 1, R,R¹, R² and R³ are hydrogen, R⁴ is 1,1-dimethylethyl, E is —NHC(O)NH—, Fis a bond, Q is —CH₂—, Ar is phenyl, Ar¹ is 3,4-chlorophenyl and thestereochemistry at the carbon to which R³ and R⁴ are attached is RS isnamed,1-{1(RS)-[4-(3,4-dichlorobenzyl)piperazin-1-yl-methyl]-2,2-dimethylpropyl}-3-phenylurea.

a compound of Formula (I) where T and U are nitrogen, n and m are 1, R,R¹, R² and R³ are hydrogen, E is —C(O)NR⁵—, R⁴ and R⁵ together form a3-pyrrolino ring, F is a bond, Q is —CH₂—, Ar is 4-methylphenyl, Ar¹ is3,4-chlorophenyl and the stereochemistry at the carbon to which R³ andR⁴ are attached is RS is named,{2-(RS)-[4-(3,4-dichlorobenzyl)piperazin-1-ylmethyl]-1-(4-methylbenzoyl)-3-pyrroline.

a compound of Formula (I) where T is nitrogen, U is carbon, n and m are1, R, R¹, R² and R³ are hydrogen, R⁴ is 1-methylethyl, E is —C(O)NH—, Fis a bond, Q is —CH₂—, Ar is 4-methylphenyl, Ar¹ is 3,4-chlorophenyl andthe stereochemistry at the carbon to which R³ and R⁴ are attached is Sis named,N-{1(S)-[4-(3,4-dichlorobenzyl)piperidin-1-yl-methyl]-2-methylpropyl}-4-methylbenzamide.

Representative Compounds of this Invention are as Follows:

I. Representative compounds of Formula (I) where T and U=nitrogen; m andn=1; R═R¹═R²═R³=hydrogen; Q=—CH₂—; E=—C(O)NH— and other groups are asdefined below are:

CPD Stereo- M. Pt. Mass. Spec # chem. Ar F R⁴ Ar¹ ° C. m/e 1 (R)4-methylphenyl bond 1-methylethyl 3,4-dichlorophenyl   232-232.4 .2HCl 2(S) 4-methylphenyl bond 1,1-dimethylethyl 3,4-dichloro- 238-242phenyl.2HCl 3 (S) 4-methoxyphenyl bond 1-methylethyl 3,4-dichloro-222.5-223   phenyl.2HCl 4 (RS) 3,4-methylene- bond 1-methylethyl3,4-dichlorophenyl 477 dioxyphenyl 5 (RS) 3,4-difluorophenyl bond1-methylethyl 3,4-dichlorophenyl 469 6 (RS) thiophen-2-yl bond1-methylethyl 3,4-dichlorophenyl 439 7 (RS) 2-pyridyl bond 1-methylethyl3,4-dichloro- 226.2-229.9 phenyl.2HCl 8 (S) 4-methylphenyl bond1-methylethyl 3,4-dichloro-   229-229.6 phenyl.2HCl 9 (RS)4-methylphenyl bond 1-methylethyl 4-nitrophenyl 424 10 (R) 3-cyanophenylbond 1-methylethyl 3,4-dichlorophenyl 458 11 (RS) 4-methylthiophenylbond 1-methylethyl 3,4-dichlorophenyl 12 (RS) 4-acetylphenyl bond1-methylethyl 3,4-dichlorophenyl 475 13 (RS) 2-benzofuranyl bond1-methylethyl 3,4-dichlorophenyl 473 14 (RS) 4-N,N-dimethyl- bond1-methylethyl 3,4-dichlorophenyl 476 aminophenyl 15 (RS) 2-indolyl bond1-methylethyl 3,4-dichlorophenyl 472 16 (RS) 4-biphenyl bond1-methylethyl 3,4-dichlorophenyl 509 17 (RS) 4-methylsulfonyl- bond1-methylethyl 3,4-dichlorophenyl 511 phenyl 18 (RS) 4-aminophenyl bond1-methylethyl 3,4-dichlorophenyl 448 19 (S) 2-naphthyl bond1-methylethyl 3,4-dichlorophenyl 483 20 (RS) 4-pyridyl bond1-methylethyl 3,4-dichloro- 150-153 phenyl.2HCl 21 (RS) 4-ethylenephenylbond 1-methylethyl 3,4-dichlorophenyl 459 22 (S) 4-methylphenyl bondcyclohexyl 3,4-dichloro- 145.9-148.2 phenyl.2HCl 23 (RS) 4-methylphenylbond n-propyl 3,4-dichloro- 199.5-203.5 phenyl.2HCl 24 (RS) 2-quinolinylbond 1-methylethyl 3,4-dichlorophenyl 484 25 (RS) thiophen-2-yl —CH₂—1-methylethyl 3,4-dichlorophenyl 453 26 (RS) 4-cyanophenyl bond1-methylethyl 4-chlorophenyl 424 27 (S) 4-amino-5-chloro-2- bond1,1-dimethylethyl 3,4-dichloro- 194.8-196.1 methoxyphenyl phenyl.2HCl 28(RS) 4-(pyrrol-1-yl)-phenyl bond 1-methylethyl 3,4-dichlorophenyl 498 29(RS) 5-nitrofuran-2-yl bond 1-methylethyl 3,4-dichlorophenyl 468 30 (RS)5-methoxyindol-2-yl bond 1-methylethyl 3,4-dichlorophenyl 502 31 (RS)3,4-methylene- bond 1-methylethyl 4-chlorophenyl 443 dioxyphenyl 32 (RS)phenyl —(CH₂)₂— 1-methylethyl 3,4-dichlorophenyl 461 33 (S)4-chlorophenyl bond methyl 3,4-dichloro-   244-246.5 phenyl.2HCl 34 (RS)4-chlorophenyl bond phenyl 3,4-dichloro- 117-183 phenyl.2HCl 35 (R)4-chlorophenyl bond cyclohexyl 3,4-dichlorophenyl 149-155 36 (RS)5-chloroindol-2-yl bond 1-methylethyl 3,4-dichlorophenyl 506 37 (RS)4-biphenyl bond 2-methylpropyl 3,4-dichlorophenyl 523 38 (RS)3-chloro-2-nitro-phenyl bond 1-methylethyl 3,4-dichlorophenyl 512 39(RS) 2,4,6-trimethylphenyl bond 1-methylethyl 3,4-dichlorophenyl 475 40(RS) 4-chlorophenyl bond benzyl 3,4-dichloro- 137-142 phenyl.2HCl 41(RS) anthraquinon-2-yl bond 1-methylethyl 3,4-dichlorophenyl 563 42 (RS)benzothiophen-2-yl bond 1-methylethyl 4-chlorophenyl 455 43 (RS)2-phenoxyphenyl bond 1-methylethyl 3,4-dichlorophenyl 525 44 (RS)4-methylphenyl ethenylene 1-methylethyl 3,4-dichlorophenyl 473 45 (RS)4-methylphenyl bond 1-methylethyl 4-chlorophenyl 46 (RS) 4-methylphenylbond 1-methylethyl 4-nitrophenyl 47 (RS) 4-methylphenyl bond1-methylethyl 3,4-difluorophenyl 48 (RS) 4-methylphenyl bond1,1-dimethylethyl 3,4-dichlorophenyl 49 (RS) 4-methylphenyl bond1-methylethyl 2,3-dichlorophenyl 50 (RS) 4-methylphenyl bond1-methylethyl 3-methyl-4-nitrophenyl 51 (RS) 4-methylphenyl bond1-methylethyl 3-chloro-4-fluorophenyl 52 (R) 4-methylphenyl bond1,1-dimethylethyl 3-chloro-4-fluorophenyl 53 (R) 4-methylphenyl bond1,1-dimethylethyl 3-methylbenzothiophen- 2-yl 54 (R) 4-methylphenyl bond1,1-dimethylethyl 1-acetylindol-3-yl 55 (R) 4-methylphenyl bond1,1-dimethylethyl 5-nitrothiophen-3-yl 56 (R) quinolin-3-yl bond1,1-dimethylethyl 3,4-dichlorophenyland are named as:

2.N-{1(S)-[4-(3,4-Dichlorobenzyl)piperazin-1-ylmethyl]-2,2-dimethylpropyl}-4-methylbenzamidedihydrochloride salt.

3.N-{1(S)-[4-(3,4-Dichlorobenzyl)piperazin-1-ylmethyl]-2-methylpropyl}-4-methoxybenzamidedihydrochloride salt.

4.N-{1(RS)-[4-(3,4-Dichlorobenzyl)piperazin-1-ylmethyl]-2-methylpropyl}-3,4-methylenedioxybenzamide.

7.N-{1(RS)-[4-(3,4-Dichlorobenzyl)piperazin-1-ylmethyl]-2-methylpropyl}picolinamidedihydrochloride salt.

8.N-{1(S)-[4-(3,4-Dichlorobenzyl)piperazin-1-ylmethyl]-2-methylpropyl}-4-methylbenzamidedihydrochloride salt.

19.N-{1(S)-[4-(3,4-Dichlorobenzyl)piperazin-1-ylmethyl]-2-methylpropyl}-2-naphthaleneamide.

25.N-{1(RS)-[4-(3,4-Dichlorobenzyl)piperazin-1-ylmethyl]-2-methylpropyl}-2-(thiophen-2-yl)acetamide.

35.N-{1(R)-cyclohexyl-2-[4-(3,4-dichlorobenzyl)piperazin-1-yl]ethyl}4-chloro-benzamide.

37.N-{1(RS)-[4-(3,4-Dichlorobenzyl)piperazin-1-ylmethyl]-3-methylbutyl}-4-phenylbenzamide.

44.N-{1(RS)-[4-(3,4-Dichlorobenzyl)piperazin-1-ylmethyl]-2-methylpropyl}-3-(4-methylphenyl)acrylamide.

II. Representative compounds of Formula (I) where T=nitrogen; U=carbon;m and n=1; R═R¹═R²═R³=hydrogen; F=bond; E=—C(O)NH— and other groups areas defined below are:

CPD Stereo- M. Pt. Mass. Spec. # chem Ar R⁴ Q Ar¹ ° C. m/e 57 (S)4-methylphenyl 1-methylethyl —CH₂— 3,4-dichlorophenyl.HCl 87-90 58 (S)4-methylphenyl 1,1-dimethylethyl —CH₂— 3,4-dichlorophenyl.HCl153.1-154.2 59 (RS) 4-methylphenyl 1-methylethyl —CH₂NHC(O)—4-amino-5-chloro-2- 515.6 methoxyphenyl 60 (RS) 4-chlorophenyl1-methylethyl —CH₂— 3,4-dichlorophenyl 467.86 61 (S) 4-chlorophenyl1,1,-dimethylethyl —CH₂— 3,4-dichlorophenyl 63-68 62 (RS) 4-methylphenyl1-methylethyl —CH₂— 4-chlorophenyl.HCl 123-128 63 (R) 4-(2-acetylamino-1-methylethyl —CH₂— 3,4-dichlorophenyl.HCl 113.3-113.9 ethyl)phenyl 64(R) 4-[(2-(R)-amino-3- 1-methylethyl —CH₂— 3,4-dichlorophenyl.2 HCl191-199 methylbutyryl- amino)ethyl)]phenyl 65 (R) 4-(2-aminoethyl)-1,1-dimethylethyl —CH₂— 3,4-dichlorophenyl.2 HCl 192-198 phenyl 66 (R)4-aminomethyl- 1,1-dimethylethyl —CH₂— 3,4-dichlorophenyl.2 HCl 476phenyl 67 (R) quinolin-3-yl 1,1-dimethylethyl —CH₂—3,4-dichlorophenyl.HCl 534 68 (R) 4-methylphenyl 1,1-dimethylethyl —CH₂—4-nitrophenyl 69 (R) pyridin-2-yl 1,1-dimethylethyl —CH₂—4-nitrophenyl.HCl 425 70 (R) pyridin-2-yl 1,1-dimethylethyl —CH₂—4-nitrophenyl 71 (R) 5-methylthiophen-2-yl 1-methylethyl —CH₂—3,4-dichlorophenyl.HCl   45-47.5 72 (R) 4-(2-aminoethyl)- 1-methylethyl—CH₂— 3,4-dichlorophenyl.2 HCl 476 phenyl 73 (R) 4-methylphenyl1,1-dimethylethyl —CH₂— 3,4-dichlorophenyl.HCl 153.1-154.2 74 (R)4-methylsulfonyl- 1,1-dimethylethyl —CH₂— 3,4-dichlorophenyl 205-214phenyl 75 (R) 5-methylthiophen- 1,1-dimethylethyl —CH₂—3,4-dichlorophenyl.HCl   161-162.5 2-yl 76 (R) 4-hydroxymethyl-1-methylethyl —CH₂— 3,4-dichlorophenyl 463 phenyland are named as:

57.N-{1(S)-[4-(3,4-Dichlorobenzyl)piperidin-1-ylmethyl]-2-methylpropyl}-4-methylbenzamidehydrochloride salt.

59.N-{1(RS)-[4-(4-Amino-5-chloro-2-methoxyphenylcarbonylaminomethyl)piperidin-1-ylmethyl]-2-methylpropyl}-4-methylbenzamide.

III. Representative compounds of Formula (I) where T and U=nitrogen; mand n=1; R═R¹═R²═R³=hydrogen; Q=—CH₂— and F=bond; E=—C(O)NR⁵—; R⁵together with R⁴ and the atoms to which they areattached=heterocycloamino group and other groups are as defined beloware:

CPD # Stereo- chem Ar

Ar¹ M. Pt. ° C. 77 (RS) 4-methylphenyl piperidino3,4-dichlorophenyl.2HCl 259.6-260   78 (R) 4-methylphenyl pyrrolidino3,4-dichlorophenyl.2HCl 249.6-250.1 79 (RS) 4-chlorophenyl piperidino3,4-dichlorophenyl.2HCl 239.6-240.5 80 (RS) 4-methylphenyl 3-pyrrolino3,4-dichlorophenyl.2HCl 242-243and are named as:

77.{1-(4-Methylbenzoyl)-2(RS)-[4-(3,4-dichlorobenzyl)piperazin-1-ylmethyl]}piperidinedihydrochloride salt.

IV. Representative compounds of Formula (I) where T and U=nitrogen; mand n=1; R¹═R²═R³=hydrogen; Q=—CH₂—; E=—NHC(O)NH— and other groups areas defined below are:

CPD Stereo- Mass Spec. # chem Ar F R + R⁴ R R⁴ Ar¹ M. Pt. m/e 81 (R)3-methoxyphenyl bond H 1-methylethyl 3,4-dichlorophenyl 478 82 (RS)2,5-dimethoxyphenyl bond H 1-methylethyl 3,4-dichlorophenyl 508 83 (RS)2-ethylphenyl bond H 1-methylethyl 3,4-dichlorophenyl 477 84 (RS)3-methoxyphenyl bond cyclohexyl 3,4-dichlorophenyl 491.46 85 (RS)3-ethylphenyl bond H 1-methylethyl 3,4-dichlorophenyl 476 86 (RS)2-ethoxyphenyl bond H 1-methylethyl 3,4-dichlorophenyl 492 87 (RS)2,3-dichlorophenyl bond H 1-methylethyl 3,4-dichlorophenyl 516 88 (RS)3-bromophenyl bond H 1-methylethyl 3,4-dichlorophenyl 526 89 (RS) phenylbond H 1-methylethyl 4-chlorophenyl 414 90 (RS) 3-chloro-2-methyl- bondH 1-methylethyl 3,4-dichlorophenyl 496 phenyl 91 (RS) 3-acetylphenylbond H 1-methylethyl 3,4-dichlorophenyl 490 92 (RS) phenyl —CH₂— H1-methylethyl 3,4-dichlorophenyl 462 93 (R) 2,4,6-trimethylphenyl bond H1-methylethyl 3,4-dichlorophenyl 271.1-275.5 94 (RS) 4-methylthiophenylbond H 2-methylpropyl 3,4-dichlorophenyl 508 95 (RS) 4-(2,2,2-trifluoro-bond H 1-methylethyl 3,4-dichlorophenyl 532 ethyl)phenyl 96 (RS)3-cyanophenyl bond H 2-methylpropyl 3,4-dichlorophenyl 487 97 (RS)3-aminocarbonyl- bond H 1-methylethyl 3,4-dichloro- 492 phenylphenyl.2HCland are named as:

82.1-{1(R)-[4-(3,4-Dichlorobenzyl)piperazin-1-ylmethyl]-2-methylpropyl}-3-(3-methoxyphenyl)urea.

1-{2(RS)-[4-(3,4-Dichlorobenzyl)piperazin-1-yl]cyclohexyl}-3-(3-methoxyphenyl)urea.

1-{1(RS)-[4-(3,4-Dichlorobenzyl)piperazin-1-ylmethyl]-2-methylpropyl}-3-benzylurea.

V. Representative compounds of Formula (I) where T=nitrogen; U=carbon; mand n=1; R═R¹═R²═R³=hydrogen; F=bond; and E=—NHC(O)NH— and other groupsare as defined below are:

CPD Stereo- Mass # chem Ar R⁴ Q Ar¹ M. Pt. Spec.   98 (S)3-methoxyphenyl 1-methylethyl —CH₂— 3,4-dichlorophenyl.HCl 97.5-99.5  99(S) 3-methoxyphenyl 1,1-dimethylethyl —CH₂— 3,4-dichlorophenyl 75.1-80.3100 (S) 4-methylphenyl 1,1-dimethylethyl —CH₂— 3,4-dichlorophenyl.HCl109.5-111   101 (S) 3-carboxyphenyl 1,1-dimethylethyl —CH₂—3,4-dichlorophenyl 506 102 (S) 3-aminocarbonyl- 1,1-dimethylethyl —CH₂—3,4-dichlorophenyl 505 phenyl 103 (S) 3,5-dimethoxy- 1-methylethyl —CH₂—3,4-dichlorophenyl.HCl 508 phenyl 104 (RS) 3,4-dimethoxy- 1-methylethyl—CH₂— 3,4-dichlorophenyl 508 phenyl 105 (R) 3-methoxyphenyl1-methylethyl —CH₂— 3,4-dichlorophenyl 478 106A (S) 3-methoxyphenyl1,1-dimethylethyl —CH₂— 3,4-dichlorophenyl.TFA 492 salt 106B (R)3,4,5-trimethoxy- 1-methylethyl —CH₂— 3,4-dichlorophenyl phenyl 106C (R)3,4,5-trimethoxy- 1,1-dimethylethyl —CH₂— 3,4-dichlorophenyl phenyl 106D(R) 3-methylsulfonyl- 1-methylethyl —CH₂— 3,4-dichlorophenyl aminophenyland are named as:

98.1-{1(S)-[4-(3,4-Dichlorobenzyl)piperidin-1-ylmethyl]-2-methylpropyl}-3-(3-methoxyphenyl)urea.

VI. Representative compounds of Formula (I) where T and U=nitrogen; mand n=1; R═R¹═R²═R³=hydrogen; Q=—CH₂—; E=NHC(S)NH— and other groups areas defined below are:

CPD Stereo- Mass Spec. # chem Ar F R⁴ Ar¹ m/e 107 (RS) 3-methylphenylbond 1-methylethyl 4-chlorophenyl 444 108 (RS) 2-fluorophenyl bond1-methylethyl 3,4-dichlorophenyl 482 109 (RS) 1-naphthyl bond1-methylethyl 4-chlorophenyl 480 110 (RS) 2-methoxyphenyl bond1-methylethyl 3,4-dichlorophenyl 494 111 (RS) 3-methylthiophenyl bond1-methylethyl 3,4-dichlorophenyl 510 112 (RS) 2,4-difluorophenyl bond2-methylpropyl 3,4-dichlorophenyl 514 113 (RS) 4-N,N-dimethylamino- bond1-methylethyl 4-chlorophenyl 473 phenyl 114 (RS) 4-methoxyphenyl —CH₂—1-methylethyl 3,4-dichlorophenyl 508 115 (RS) 4-trifluoromethylphenylbond 1-methylethyl 4-chlorophenyl 498 116 (RS) 3-chlorophenyl bond2-methylpropyl 3,4-dichlorophenyl 512and are named as:

107.1-{1(RS)-[4-(4-Chlorobenzyl)piperazin-1-yl]-2-methylpropyl}-3-(3-methylphenyl)-2thiourea.

111.1-{1(RS)-[4-(3,4-Dichlorobenzyl)piperazin-1-yl]-3-methylbutyl}-3-(2,4-difluorophenyl)-2-thiourea.

VII. Representative compounds of Formula (I) where T and U=nitrogen; mand n=1; R═R¹═R²═R³=hydrogen; F=bond; Q=—CH₂—; E=—SO₂NH— and othergroups are as defined below are:

CPD Stereo- Mass Spec. # chem Ar R⁴ Ar¹ m/e 117 (R) 4-fluorophenyl1-methylethyl 3,4-dichlorophenyl 487 118 (RS) 4-chlorophenyl1-methylethyl 4-chlorophenyl 469 119 (R) 4-nitrophenyl 1-methylethyl3,4-dichlorophenyl 514 120 (R) thiophen-2-yl 1-methylethyl4-chlorophenyl 441 121 (RS) 4-trifluorophenyl 1-methylethyl4-chlorophenyl 503 122 (RS) 2,4-dichlorophenyl 2-methylpropyl3,4-dichlorophenyl 511 123 (RS) 3-bromophenyl 2-methylpropyl3,4-dichlorophenyl 561 124 (R) 4-methylphenyl 1-methylethyl4-chlorophenyl 449 125 (R) 2-chloro-4-fluoro- 1-methylethyl4-chlorophenyl 487 phenyl 126 (R) 2-nitro-4-trifluoro- 1-methylethyl4-chlorophenyl 480 methylphenyl (M + —CF3) 127 (RS) 3,4-dimethoxyphenyl1-methylethyl 4-chlorophenyl 495and are named as:

117.N-{1(R)-[4-(3,4-Dichlorobenzyl)piperazin-1-ylmethyl]-2-methylpropyl}-4-fluorobenzenesulfonamide.

120.N-{1(RS)-[4-(3,4-Dichlorobenzyl)piperazin-1-ylmethyl]-3-methylbutyl}-2,4-dichlorobenzenesulfonamide.

VIII. Representative compounds of Formula (I) where T and U=nitrogen; mand n=1; R¹═R²═R³=hydrogen; F=bond; Q=—CH₂—; E=—NHC(O)— and other groupsare as defined below are:

CPD Stereo- Mass Spec. # chem Ar R + R⁴ R⁴ R Ar¹ M. Pt. m/e 128 (RS)4-methylphenyl methyl H 3,4-dichlorophenyl.2HCl 256.2-256.7 129 (RS)phenyl methyl H 3,4-dichlorophenyl.2HCl 262.5-262.9 130 1(R), 2(R)4-methylphenyl cyclopentyl 3,4-dichlorophenyl.2HCl 446 131 1(R), 2(S)4-methylphenyl cyclopentyl 3,4-dichlorophenyland are named as:

128.2-(RS)-[4-(3,4-Dichlorobenzyl)piperazin-1-ylmethyl]-N-(4-methylphenyl)propionamidedihydrochloride salt.

130.2-(R)-[4-(3,4-Dichlorobenzyl)piperazin-1-ylmethyl]-N-(4-methylphenyl)cyclopentane-1-(R)-carboxamidedihydrochloride salt.

IX. Representative compounds of Formula (I) where T=carbon; U=nitrogen;n=1; R═R¹═R²═R³=hydrogen; F=bond; and Q=—CH₂—; E=—C(O)NH— and othergroups are as defined below are:

CPD Stereo- # chem Ar E R⁴ m R Ar¹ M. Pt. 132 (RS) 4-methoxyphenyl—NHC(O)NH— 1-methylethyl 0 H 3,4-dichlorophenyl 161.4-161.8 133 (RS)4-methylphenyl —C(O)NH— 1-methylethyl 1 H 3,4-dichlorophenyl 233.9-235.5and are named as:

133.N-{1-[1(RS)-[1-(3,4-Dichlorobenzyl)piperidin-4-ylmethyl]-2-methylpropyl}-4-methylbenzamide.

PREFERRED EMBODIMENTS

While the broadest definition of this invention is set forth in theSummary of the Invention, certain compounds of Formula (I) arepreferred.

A preferred group of compounds are those wherein:

-   -   n is 1;    -   m is 0 or 1;    -   F is a bond;    -   Q is an alkylene chain of between 1 to 6 carbon atoms inclusive,        more preferably methylene; and    -   E is —C(O)N(R⁵)—, —SO₂N(R⁵)—, —N(R⁶)C(O)N(R⁵)— or —N(R⁶)C(O)—.

Within the above preferred group a more preferred group of compounds isthat wherein:

-   -   R, R¹, R² and R³ are hydrogen; and    -   E is —C(O)N(R⁵)—, preferably —C(O)NH—.

Another more preferred group of compounds is wherein:

-   -   R, R¹, R² and R³ are hydrogen; and    -   E is —N(R⁶)C(O)N(R⁵)—, preferably —NHC(O)NH—.

Within these preferred and more preferred groups of compounds aparticularly preferred group of compounds is that wherein T and U arenitrogen;

Another particularly preferred group of compounds is that wherein T isnitrogen and U is carbon;

Yet another particularly preferred group of compounds is that wherein Tis carbon and U is nitrogen;

Within the above preferred, more preferred and particularly preferredgroups where T and U are both nitrogen or where T is nitrogen and U iscarbon, most preferred compounds are those wherein:

R⁴ is alkyl or heteroalkyl, preferably 1-methylethyl, 1,1-dimethylethyl,2-methylpropyl, 3-hydroxypropyl, 1-hydroxyethyl or 2-hydroxyethyl, morepreferably 1-methylethyl or 1,1-dimethylethyl;

Ar is a heteroaryl or aryl ring, preferably a pyridin-2-yl,pyridin-3-yl, quinolin-3-yl or 5-methylthiophen-2-yl ring or a phenylring optionally substituted with one, two or three substituents selectedfrom alkyl, heteroalkyl, alkoxy, —COR (where R is alkyl), —SO₂R (where Ris alkyl, amino or mono or disubstituted amino), methylenedioxy,hydroxy, halo, acylamino, amino, mono- or disubstituted amino, —CONR′R″,-(alkylene)-CONR′R″ (where R′ and R″ are hydrogen or alkyl), —COOR,-(alkylene)-COOR (where R is hydrogen or alkyl) or —NRSO₂R′ (where R ishydrogen or alkyl and R′ is alkyl, amino, mono or disubstituted amino),more preferably a phenyl ring optionally substituted with one, two orthree substituents selected from methyl, methoxy, fluoro, chloro,dimethylamino, acetyl, hydroxy, amino, methylenedioxy, —SO₂Me,2-acetylaminoethyl, 2-[(R)-amino-3-methylbutyrylamino]ethyl,2-aminoethyl, aminomethyl, hydroxymethyl, aminocarbonyl, —COOH,carboxymethyl, methoxycarbonylmethyl, aminocarbonylmethyl,dimethylaminocarbonylmethyl, acetylaminomethyl, methylsulfonylamino,methylsulfonylaminomethyl, dimethylaminosulfonylaminomethyl, ordimethylamino, most preferably phenyl, 4-chlorophenyl,3,4-difluorophenyl, 4-methylphenyl, 3-methoxyphenyl, 4-methoxyphenyl,4-hydroxyphenyl, 3,4-methylenedioxyphenyl, 4-methylsulfonylphenyl,4-[(2-acetylamino)ethyl]phenyl,4-{2-[(R)-amino-3-methylbutyrylamino]ethyl}phenyl,4-(2-aminoethyl)phenyl, 4-(aminomethyl)phenyl, 4-(hydroxymethyl)phenyl,3-aminocarbonylphenyl, 3-carboxyphenyl, 2,5-dimethoxyphenyl,3,5-dimethoxyphenyl, 3,4-dimethoxyphenyl, 3,4,5-trimethoxyphenyl,3-aminocarbonylmethylphenyl, 3-acetylaminomethyphenyl,3-carboxymethylphenyl, 3-methylsulfonylaminophenyl,3-methylsulfonylaminomethylphenyl or 4-aminophenyl; and

Ar¹ is a heteroaryl or aryl ring, preferably 1-acetylindol-3-yl,3-methylbenzothiophen-2-yl or 5-nitrothiophen-3-yl, or a phenyl ringoptionally substituted with one, two or three substituent selected fromalkyl, heteroalkyl, alkoxy, halo, trifluoromethyl, nitro, or mono- ordisubstituted amino, more preferably a phenyl ring substituted with one,or two substituents selected from methyl, methoxy, chloro, fluoro,trifluoromethyl or nitro, most preferably 4-nitrophenyl,4-trifluoromethylphenyl, 4-chlorophenyl, 3,4-difluorophenyl,2,3-dichlorophenyl, 3-methyl-4-nitrophenyl, 3-chloro-4-fluorophenyl or3,4-dichlorophenyl.

Within the above preferred, more preferred and particularly preferredgroups where T is carbon and U is nitrogen, most preferred compounds arethose wherein:

R⁴ is alkyl or heteroalkyl, preferably methyl, 1-methylethyl,1,1-dimethylethyl, 2-methylpropyl, 3-hydroxypropyl, 1-hydroxyethyl or2-hydroxyethyl.

Ar is a heteroaryl or aryl ring, preferably a pyridin-2-yl,pyridin-3-yl, quinolin-3yl or 5-methylthiophen-2-yl ring or a phenylring optionally substituted with one, two or three substituents selectedfrom alkyl, heteroalkyl, alkoxy, —COR (where R is alkyl), —SO₂R (where Ris alkyl, amino or mono or disubstituted amino), methylenedioxy,hydroxy, halo, acylamino, amino, mono- or disubstituted amino, —CONR′R″,-(alkylene)-CONR′R″ (where R′ and R″ are hydrogen or alkyl), —COOR,-(alkylene)-COOR (where R is hydrogen or alkyl) or —NRSO₂R′ (where R ishydrogen or alkyl and R′ is alkyl, amino, mono or disubstituted amino),more preferably a phenyl ring optionally substituted with one, two orthree substituents selected from methyl, methoxy, fluoro, chloro,dimethylamino, acetyl, hydroxy, amino, methylenedioxy, —SO₂Me,2-acetylaminoethyl, 2-[(R)-amino-3-methylbutyrylamino]ethyl,2-aminoethyl, aminomethyl, hydroxymethyl, aminocarbonyl, —COOH,carboxymethyl, methoxycarbonylmethyl, aminocarbonylmethyl,dimethylaminocarbonylmethyl, acetylaminomethyl, methylsulfonylamino,methylsulfonylaminomethyl, dimethylaminosulfonylaminomethyl, ordimethylamino, most preferably phenyl, 4-chlorophenyl,3,4-difluorophenyl, 4-methylphenyl, 3-methoxyphenyl, 4-methoxyphenyl,4-hydroxyphenyl, 3,4-methylenedioxyphenyl, 4-methylsulfonylphenyl,4-[(2-acetylamino)ethyl]phenyl,4-{2-[(R)-amino-3-methylbutyrylamino]ethyl}phenyl,4-(2-aminoethyl)phenyl, 4-(aminomethyl)phenyl, 4-(hydroxymethyl)phenyl,3-aminocarbonylphenyl, 3-carboxyphenyl, 2,5-dimethoxyphenyl,3,5-dimethoxyphenyl, 3,4-dimethoxyphenyl, 3,4,5-trimethoxyphenyl,3-aminocarbonylmethylphenyl, 3-acetylaminomethyphenyl,3-carboxymethylphenyl, 3-methylsulfonylaminophenyl,3-methylsulfonylaminomethylphenyl or 4-aminophenyl; and

Ar¹ is a heteroaryl or aryl ring, preferably 1-acetylindol-3-yl,3-methylbenzothiophen-2-yl, 5-nitrothiophen-3-yl or a phenyl ringoptionally substituted with one, two or three substituent selected fromalkyl, heteroalkyl, alkoxy, halo, trifluoromethyl, nitro, or mono- ordisubstituted amino, more preferably a phenyl ring substituted with one,or two substituents selected from methyl, methoxy, chloro, fluoro,trifluoromethyl or nitro, most preferably 4-nitrophenyl,4-trifluoromethylphenyl, 4-chlorophenyl, 3,4-difluorophenyl,2,3-dichlorophenyl, 3-methyl-4-nitrophenyl, 3-chloro-4-fluorophenyl or3,4-dichlorophenyl.

Exemplary Particularly Preferred Compounds of the Invention at Presentare:

N-{1-(S)-[4-(3,4-Dichlorobenzyl)piperazin-1-ylmethyl]-2-methylpropyl}-4-methylbenzamidedihydrochloride salt.

N-{1-(S)-[4-(3,4-Dichlorobenzyl)piperazin-1-ylmethyl]-2,2-dimethylpropyl}-4-methylbenzamidedihydrochloride salt.

1-{1-(R)-[4-(3,4-Dichlorobenzyl)piperazin-1-ylmethyl]-2-methylpropyl}-3-(3-methoxyphenyl)urea.

N-{1-(RS)-[4-(3,4-Dichlorobenzyl)piperazin-1-ylmethyl]-2-methylpropyl}-3,4-methylenedioxybenzamide.

N-{1-(S)-[4-(3,4-Dichlorobenzyl)piperazin-1-ylmethyl]-2,2-dimethylpropyl}-4-methylsulfonylbenzamidedihydrochloride salt.

N-{1-(S)-[4-(3,4-Dichlorobenzyl)piperazin-1-ylmethyl]-2,2-dimethylpropyl}-4-acetylbenzamidedihydrochloride salt.

N-{1-(S)-[4-(3,4-Dichlorobenzyl)piperazin-1-ylmethyl]-2,2-dimethylpropyl}4-dimethylaminobenzamidedihydrochloride salt.

N-{1-(S)-[4-(4-Nitrobenzyl)piperidin-1-ylmethyl]-2,2-dimethylpropyl}-4-methylsulfonylbenzamidehydrochloride salt.

N-{1-(S)-[4-(3,4-Dichlorobenzyl)piperazin-1-ylmethyl]-2,2-dimethylpropyl}-5-methylthiophene-2-carboxamidedihydrochloride salt.

N-{1-(RS)-[4-(3,4-Dichlorobenzyl)piperazin-1-ylmethyl]-2,2-dimethylpropyl}-4-methoxybenzamide.

N-{1-(RS)-[4-(3,4-Dichlorobenzyl)piperazin-1-ylmethyl]-2,2-dimethylpropyl}-3-cyanobenzamide.

N-{1-(RS)-[4-(3,4-Dichlorobenzyl)piperazin-1-ylmethyl]-2-methylpropyl}-3,4-difluorobenzamide.

N-{1(-RS)-[3-Methyl-4-(3,4-dichlorobenzyl)piperazin-1-ylmethyl]-2-methylpropyl}-4-methylbenzamidedihydrochloride salt.

N-{4-(R)-[4-(3,4-Dichlorobenzyl)piperidin-1-ylmethyl]-2-methylpropyl}-1-[4-(2-acetylaminoethyl)]benzamidedihydrochloride salt.

4-[2-(2-(R)-Amino-3-methylbutyrylamino)ethyl]-N-{1-[4-(3,4-dichlorobenzyl)piperidin-1-ylmethyl]-2-methylpropyl}benzamidedihydrochloride salt.

N-{4-(R)-[4-(3,4-Dichlorobenzyl)piperidin-1-ylmethyl]-2,2-dimethylpropyl}-1-[4-(2-aminoethyl)]benzamidedihydrochloride salt.

N-{4-(R)-[4-(3,4-Dichlorobenzyl)piperidin-1-ylmethyl]-2,2-dimethylpropyl}-1-(4-aminomethyl)benzamidedihydrochloride salt.

N-{4-(S)-[4-(3,4-Dichlorobenzyl)piperidin-1-ylmethyl]-2,2-dimethylpropyl}-1-(3,4-methylenedioxy)benzamidedihydrochloride salt.

1-{1-(RS)-[4-(3,4-Dichlorobenzyl)piperazin-1-ylmethyl]-2-methylpropyl}-3-(3-aminocarbonylphenyl)urea.

N-{4-(R)-[4-(3,4-Dichlorobenzyl)piperidin-1-ylmethyl]-2,2-dimethylpropyl}-1-quinoline-3-carboxamidehydrochloride salt.

1-{1-(S)-[4-(3,4-Dichlorobenzyl)piperidin-1-ylmethyl]-2,2-dimethylpropyl}-3-(3-carboxyphenyl)urea.

1-{1-(S)-[4-(3,4-Dichlorobenzyl)piperidin-1-ylmethyl]-2,2-dimethylpropyl}-3-(3-aminocarbonylphenyl)urea.

1-{1-(S)-[4-(3,4-Dichlorobenzyl)piperidin-1-ylmethyl]-2-methylpropyl}-3-(3-methylsulfonylphenyl)urea.

1-{1-(R)-[4-(3,4-Dichlorobenzyl)piperidin-1-ylmethyl]-2-methylpropyl}-3-(3,5-dimethoxyphenyl)ureahydrochloride salt.

1-{1-(R)-[4-(3,4-Dichlorobenzyl)piperidin-1-ylmethyl]-2-methylpropyl}-3-(3,4-dimethoxyphenyl)urea.

N-{1-(S)-[4-(4-Chlorobenzyl)piperazin-1-ylmethyl]-2-methylpropyl}-4-methylbenzamide.

N-{1-(S)-[4-(3,4-Dichlorobenzyl)piperidin-1-ylmethyl]-2-methylpropyl}-4-guanidinomethylbenzamide.

N-{1-(RS)-[4-(4-Nitrobenzyl)piperazin-1-ylmethyl]-2-methylpropyl}-4-methylbenzamide.

N-{1-(RS)-[4-(3,4-Difluorobenzyl)piperazin-1-ylmethyl]-2-methylpropyl}-4-methylbenzamide.

N-{1-(RS)-[4-(3,4-Dichlorobenzyl)piperazin-1-ylmethyl]-2,2-dimethylpropyl}-4-methylbenzamide.

N-{1-(RS)-[4-(2,3-Dichlorobenzyl)piperazin-1-ylmethyl]-2-methylpropyl{-4-methylbenzamide.

N-{1-(RS)-[4-(3-Methyl-4-nitrobenzyl)piperazin-1-ylmethyl]-2-methylpropyl}-4-methylbenzamide.

N-{1-(RS)-[4-(3-Chloro-4-fluorobenzyl)piperazin-1-ylmethyl]-2-methylpropyl}-4-methylbenzamide.

N-{1-(R)-[4-(3-Chloro-4-fluorobenzyl)piperazin-1-ylmethyl]-2,2-dimethylpropyl}-4-methylbenzamide.

N-{1-(R)-[4-(3-Methylbenzothiophen-2-ylmethyl)piperazin-1-ylmethyl]-2,2-dimethylpropyl}-4-methylbenzamide.

N-{1-(R)-[4-(1-Acetylindol-3-ylmethyl)piperazin-1-ylmethyl]-2,2-dimethylpropyl-4-methylbenzamide.

N-{1-(R)-[4-(5-Nitrothiophen-3-ylmethyl)piperazin-1-ylmethyl]-2,2-dimethylpropyl}-4-methylbenzamide.

N-{1-(R)-[4-(4-Nitrobenzyl)piperazin-1-ylmethyl]-2-methylpropyl}-4-methylbenzamide.

N-{4-(R)-[4-(4-Nitrobenzyl)piperidin-1-ylmethyl]-2,2-dimethylpropyl}-1-pyridine-2-carboxamidehydrochloride salt.

N-{4-(R)-[4-(4-Nitrobenzyl)piperidin-1-ylmethyl]-2,2-dimethylpropyl}-1-pyridine-2-carboxamide.

N-{4-(R)-[4-(3,4-Dichlorobenzyl)piperazin-1-ylmethyl]-2,2-dimethylpropyl}-1-quinoline-3-carboxamide.

1-{1-(R)-[4-(3,4-Dichlorobenzyl)piperidin-1-ylmethyl]-2-methylpropyl}-3-(3-methoxyphenyl)urea.

N-{4-(R)-[4-(3,4-Dichlorobenzyl)piperidin-1-ylmethyl]-2-methylpropyl}-1-(3-methyl)thiophene-2-carboxamidehydrochloride salt.

N-{4-(R)-[4-(3,4-Dichlorobenzyl)piperidin-1-ylmethyl]-2-methylpropyl}-1-[4-(2-aminoethyl)]benzamidedihydrochloride salt.

N-{4-(RS)-[4-(3,4-Dichlorobenzyl)piperidin-1-ylmethyl]-2-methylpropyl}-1-(4-methyl)benzamide.

N-{4-(R)-[4-(3,4-Dichlorobenzyl)piperidin-1-ylmethyl]-2,2-dimethylpropyl}-1-(4-methyl)benzamidehydrochloride salt.

N-{4-(R)-[4-(3,4-Dichlorobenzyl)piperidin-1-ylmethyl]-2,2-dimethylpropyl}-1-(4-methylsulfonyl)benzamide.

N-{4-(S)-[4-(3,4-Dichlorobenzyl)piperidin-1-ylmethyl]-2,2-dimethylpropyl}-1-(5-methylthiophene-2-carboxamidehydrochloride salt.

N-{4-(R)-[4-(3,4-Dichlorobenzyl)piperidin-1-ylmethyl]-2,2-dimethylpropyl}-1-(4-hydroxymethyl)benzamide.

1-{1-(R)-[4-(3,4-Dichlorobenzyl)piperidin-1-ylmethyl]-2,2-dimethylpropyl}-3-(3-methoxyphenyl)ureatrifluoroacetate salt.

1-{1-(R)-[4-(3,4-Dichlorobenzyl)piperidin-1-ylmethyl]-2-methylpropyl}-3-(3,4,5-trimethoxyphenyl)urea.

1-{1-(R)-[4-(3,4-Dichlorobenzyl)piperidin-1-ylmethyl]-2,2-dimethylpropyl}-3-(3,4,5-trimethoxyphenyl)urea.

1-{1-(R)-[4-(3,4-Dichlorobenzyl)piperidin-1-ylmethyl]-2-methylpropyl}-3-(3-methylsulfonylaminophenyl)urea.

1-{1-(R)-[4-(3,4-Dichlorobenzyl)piperidin-1-ylmethyl]-2-methylpropyl}-3-(3-methylsulfonylaminomethylphenyl)urea.

1-{1-(R)-[4-(3,4-Dichlorobenzyl)piperidin-1-ylmethyl]-2-methylpropyl}-3-(3-acetylaminophenyl)urea.

1-{1-(R)-[4-(3,4-Dichlorobenzyl)piperidin-1-ylmethyl]-2-methylpropyl}-3-(3-acetylaminomethylphenyl)urea.

1-{1-(R)-[4-(3,4-Dichlorobenzyl)piperidin-1-ylmethyl]-2-methylpropyl}-3-(3-N-methylsulfonyl-N-methylaminophenyl)urea.

1-{1-(R)-[4-(3,4-Dichlorobenzyl)piperidin-1-ylmethyl]-2-methylpropyl}-3-(3-dimethylaminosulfonylaminophenyl)urea.

1-{1-(R)-[4-(3,4-Dichlorobenzyl)piperidin-1-ylmethyl]-2-methylpropyl}-3-(3-dimethylaminosulfonylaminomethylphenyl)urea.

1-{1-(R)-[4-(3,4-Dichlorobenzyl)piperidin-1-ylmethyl]-2-methylpropyl}-(3-methoxyphenyl)-3-methyl-urea.

1-{1-(R)-[4-(3,4-Dichlorobenzyl)piperidin-1-ylmethyl]-2-methylpropyl}-3-(3-acetylphenyl)urea.

1-{1-(R)-[4-(3,4-Dichlorobenzyl)piperidin-1-ylmethyl]-2-methylpropyl}-3-(3aminomethylphenyl)urea.

1-{1-(R)-[4-(3,4-Dichlorobenzyl)piperidin-1-ylmethyl]-2-methylpropyl}-3-(3-dimethylaminomethylphenyl)urea.

1-{1-(R)-[4-(3,4-Dichlorobenzyl)piperidin-1-ylmethyl]-2-methylpropyl}-3-(3-carboxymethylphenyl)urea.

1-{1-(R)-[4-(3,4-Dichlorobenzyl)piperidin-1-ylmethyl]-2-methylpropyl}-3-(3-methoxycarbonylmethylphenyl)urea.

1-{1-(R)-[4-(3,4-Dichlorobenzyl)piperidin-1-ylmethyl]-2-methylpropyl}-3-(3-aminocarbonylmethylphenyl)urea.

1-{1-(R)-[4-(3,4-Dichlorobenzyl)piperidin-1-ylmethyl]-2-methylpropyl}-3-(3-dimethylaminocarbonylmethylphenyl)urea.

GENERAL SYNTHETIC SCHEME

The compounds of the present invention can be prepared in a number ofways known to one skilled in the art. Preferred methods include, but arenot limited to, the general synthetic procedures described below.

The starting materials and reagents used in preparing these compoundsare either available from commercial suppliers such as Aldrich ChemicalCo., (Milwaukee, Wis., USA), Bachem (Torrance, Calif., USA),Emka-Chemie, or Sigma (St. Louis, Mo., USA) or are prepared by methodsknown to those skilled in the art following procedures set forth inreferences such as Fieser and Fieser's Reagents for Organic Synthesis,Volumes 1-17 (John Wiley and Sons, 1991); Rodd's Chemistry of CarbonCompounds, Volumes 1-5 and Supplementals (Elsevier Science Publishers,1989), Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991),March's Advanced Organic Chemistry, (John Wiley and Sons, 1992), andLarock's Comprehensive Organic Transformations (VCH Publishers Inc.,1989). These schemes are merely illustrative of some methods by whichthe compounds of this invention can be synthesized, and variousmodifications to these schemes can be made and will be suggested to oneskilled in the art having referred to this disclosure.

The starting materials and the intermediates of the reaction may beisolated and purified if desired using conventional techniques,including but not limited to filtration, distillation, crystallization,chromatography, and the like. Such materials may be characterized usingconventional means, including physical constants and spectral data.

Synthesis of Compounds of Formula (I)

In general, compounds of Formula (I) where n, m, R, R¹, R², R³, R⁴, R⁵,Q and Ar¹ are as defined in the Summary of the Invention are preparedfrom aminoalkyl derivatives of Formulae II(a-c) and carboxyalkylderivatives of Formulae II(d-f) as shown in FIG. 1 below.

Synthesis of compounds of Formulae II(a-f) and their conversion tocompounds of Formula (I) are described in detail in Schemes A-E and F-J,respectively.

Synthesis of Compounds of Formulae II(a-f) Preparation of Compounds ofFormula IIa

A compound of Formula IIa where n is 1 or 2, m is at least 1 and R, R²,R³, R⁴, R⁵, Q and Ar¹ are as defined in the Summary of the invention isprepared as shown in Scheme A below.

In general, compounds of Formula IIa are prepared in two steps by firstconverting a compound of formula 1 or 2 to an N-protected aminoalkylderivative of formula 3 via methods (a) or (b) respectively, followed byremoval of the amino protecting group in 3, as described in detailbelow.

Preparation of Compounds of Formula 3

Method (a)

In method (a), an N-protected aminoalkyl derivative of formula 3 wherePG is an amino protecting group (e.g., tert-butoxycarbonyl (BOC),benzyloxycarbonyl (CBZ), benzyl, and the like) is prepared by reacting acompound of formula 1 with a compound of formula 4PG-N(R⁵)CR³R⁴(CHR)_(m−1)X  4where X is an aldehyde (—CHO), ketone (—C(O)R where R is alkyl), carboxy(—COOH) or a reactive carboxy derivative e.g., acid halide. The reactionconditions employed depend on the nature of the X group. If X is analdehyde or a ketone group, the reaction is carried out under reductiveamination reaction conditions i.e., in the presence of a suitablereducing agent (e.g., sodium cyanoborohydride, sodiumtriacetoxyborohydride, and the like) and an organic acid (e.g., glacialacetic acid, trifluoroacetic acid, and the like) at ambient temperatureto give 3 directly. Suitable solvents for the reaction are halogenatedhydrocarbons (e.g., 1,2-dichloroethane, chloroform, and the like). If Xis a carboxy group, the reaction is carried out in the presence of asuitable coupling agent (e.g., N,N-dicyclohexylcarbodiimide,1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, and the like) in asuitable organic solvent (e.g., methylene chloride, tetrahydrofuran, andthe like) to give an amide intermediate. Reduction of the amideintermediate with a suitable reducing agent (e.g., diborane, lithiumaluminum hydride, and the like) in an ethereal organic solvent such asether or tetrahydrofuran then provides a compound of formula 3. If X isan acid derivative such as an acid chloride, the reaction is carried outin the presence of a suitable base such as triethylamine, pyridine in anorganic solvent (e.g., methylene chloride, dichloroethane,N,N-dimethylformamide, and the like) to give an amide intermediate whichis reduced to the corresponding compound of formula 3 as describedabove.

In general, compounds of formula 4 are either commercially available orthey can be prepared by methods well known in the field of organicchemistry. Some examples of such procedures are illustrated anddescribed in detail below.

-   -   (i) An aldehyde of 4 (X is a —CHO) where m−1=0 is conveniently        prepared from the corresponding natural or unnatural α-amino        acid of formula 4 where m−1=0 and X is a carboxy group by        reduction of the carboxy group to an aldehyde group with a        suitable reducing agent such as DEBAL-H®. An aldehyde of formula        4 where m−1=1 or 2 can be prepared, if desired, from an aldehyde        or ketone (X=—COR where R is alkyl) of formula 4 where m−1=0        under Wittig reaction conditions. For example, an aldehyde 4        where m−1=1 and R is hydrogen or alkyl is prepared by condensing        the corresponding aldehyde or ketone of formula 4 where m−1=0        with a Wittig reagent derived from chloromethyl methyl ether,        followed by acidic hydrolysis of the resulting enol ether        intermediate. An aldehyde 4 where m−=2 and R are hydrogen or        alkyl can be prepared by condensing the corresponding aldehyde        or ketone 4 where m−1=0 with a Wittig reagent derived from        bromoacetate or 2-bromopropionate respectively, followed by        sequential reduction of the double bond and the ester group in        the resulting α,β-unsaturated ester intermediate. The double        bond is reduced under hydrogenation reaction conditions and the        ester group is reduced to the aldehyde group with reducing agent        such as DIBAL-H®. The ketone of formula 4 where m−1=0 can be        prepared from the α-amino acids of formula 4 by converting the        α-amino acids 4 to a Weinreb amide, followed by treatment with        an organometallic reagent such as a Grignard reagent or an        organolithium reagent of formula RMgBr or RLi (where R is an        alkyl group) respectively.

Generally, both natural and unnatural amino acids are commerciallyavailable from vendors such as Aldrich and Bachem. Examples of unnaturalamino acids include, homoserine, homocysteine, N-α-methylarginine,norleucine, N-methylisoleucine, phenylglycine, hydroxyproline,pyroglutamine, ornithine, 2-aminoisobutyric acid, 2-aminobutyric acid,β-cyclohexylalanine, 3-(1-naphthyl)alanine, 3-(2-naphthyl)alanine,citrulline, pipecolinic acid, piperazic acid, 4-chlorophenylalanine,4-fluorophenylalanine and sarcosine. Synthesis of α-amino acids 4 whereR³ and R⁵ together form a morpholino ring and thiomorpholino ring and R⁴is hydrogen is described in Kogami, Y., Okawa, K., Bull Chem. Soc. Jpn.,60, 2963, (1987).

-   -   (ii) Compounds of formula 4 where X is a carboxy group and m−1>0        can be prepared from the corresponding aldehydes of formula 4 (X        is —CHO), prepared as described in (i) above, by oxidation of        the aldehyde group with a suitable oxidizing agent (e.g.,        potassium permanganate and the like). Alternatively, they can be        prepared from the α,β-unsaturated esters formed in the Wittig        reaction, see (i) above, by reduction of the double bond        followed by the hydrolysis of the ester group by methods well        known in the art.    -   (iii) Compounds of formula 4 where X is —C(O)R (where R is        alkyl) and m−=0, 1 or 2 can be prepared by alkylating the        corresponding aldehyde of formula 4 (X is —CHO) with a Grignard        reagent followed by oxidation of the resulting alcohol with a        suitable oxidizing agent such as pyridinium dichromate and the        like. Alternatively, they can be prepared from the corresponding        acid of formula 4 as described in (i) above.    -   (iv) Compounds of formula 4 where X is an acid derivative e.g.,        an acid chloride, can be prepared from the corresponding acids        of formula 4 (X is —COOH), prepared as described in (iii) above,        by chlorinating the carboxy group with a suitable chlorinating        agent (e.g., oxalyl chloride, thionyl chloride and the like) in        a suitable organic solvent such as methylene chloride and the        like.

Alternatively, a compound of formula 3 can be prepared directly byreacting a compound of formula 1 with an alkylating agent of formula 5PG-N(R⁵)CR³R⁴(CHR)_(m)Y  5where Y is a leaving group under alkylating conditions such as halo(e.g., chloro, bromo or iodo) or sulfonyloxy group (e.g.,methylsulfonyloxy or 4-methylphenylsulfonyloxy ortrifluoromethylsulfonyloxy). The reaction is carried out in the presenceof a base such as sodium carbonate, sodium hydride, triethylamine andthe like. Suitable solvents are aprotic organic solvents such astetrahydrofuran, N,N-dimethylformamide, and the like.

In general, compounds of formula 5 where Y is a halo or a sulfonyloxygroup can be prepared from compounds of formula 4 by reducing thealdehyde, ketone or carboxy group to an alcohol, followed by treatmentwith a suitable halogenating agent (e.g., thionyl chloride, thionylbromide, carbon tetrabromide in the presence of triphenylphosphine, andthe like) or sulfonylating agent (e.g., methylsulfonyl chloride,para-toluenesulfonyl chloride and triflic anhydride) respectively.Suitable aldehyde, ketone or carboxy reducing agents include lithiumaluminum hydride, borane and the like.

In some instances, a compound of Formula IIa can be prepared by reactinga compound of formula 1 with a conjugated nitro-olefin under Michaeladdition reaction conditions, followed by reduction of the nitro groupunder standard hydrogenation reaction conditions. Conjugatednitro-olefins are commercially available or can be prepared by knownliterature procedures e.g., see Corey, E. J. et al., J. Am. Chem. Soc,100(19), 8294-5, (1978). A detailed description of the synthesis of anN-alkylaminopiperazine of Formula IIa by this method is given in Example2.

Method (b)

In method (b), an N-protected aminoalkyl derivative of formula 3 isprepared by reacting a compound of formula 2 with a compound of formula6Ar¹—Q—J  6(where J is an X or Y group as defined above) utilizing the reactionconditions described in method (a) above. Method (b) is particularlysuitable for preparing compounds of Formula IIa where Q contains anamido or a carbonyl group.

In general, compounds of formula 6 are commercially available or can beprepared by methods well known in the art. For example, aralkyl halidesand aralkyl acids such as benzyl bromide, 3,4-dichlorobenzyl bromide,phenylacetic acids and 2-phenylpropionic acids are commerciallyavailable. Others can be prepared from suitable starting materials suchas phenylacetic acid, phenylpropanol, 2-pyridineethanol, nicotinic acidetc., by following procedures described for the synthesis of compoundsof formula 4 and 5 in method (a) above. Compounds of formula 6 where Qis an alkylene chain interrupted by an amido group and J is a halo orsufonyloxy group can be prepared by following the procedures describedin U.S. Pat. No. 4,880,808.

Conversion of Compounds of Formula 3 to compounds of Formula IIa

In Step 2, the N-protected aminoalkyl derivatives 3, formed in Step 1via method (a) or (b), are converted to a compound of Formula IIa byremoval of the amino protecting group. The conditions utilized depend onthe nature of the protecting group. For example, if the protecting groupis the tert-butoxycarbonyl group it is removed under acidic hydrolysisreaction condition whereas if it is the benzyl group it is removed undercatalytic hydrogenation reaction conditions.

A compound of Formula IIa where R⁵ is other than hydrogen can beprepared, if desired, by alkylating the corresponding compound ofFormula IIa where R⁵ is hydrogen with an alkylating agent R⁵Y where Y isa leaving group under alkylating conditions, utilizing the reactionconditions described in method (a) of Scheme A.

Compounds of formula 1 and 2 are prepared as shown below by reacting apiperazine or homopiperazine of formula 7 with a compound of formula 6,or 4 or 5 respectively, followed by the removal of the amino protectinggroup, utilizing the reaction conditions described in method (a) above.

Piperazines and homopiperazines of formula 7 such as piperazine, 2 or3-methylpiperazines, homopiperazine are commercially available.Piperazines 7 can also be prepared by following the procedures describedin the European Pat. Pub. No. 0,068,544 and U.S. Pat. No. 3,267,104.Detailed descriptions of the synthesis of a compound of formula 1 wheren=1 by this method is given in Examples 1, 5 and 7.

Preparation of Compounds of Formula IIb

A compound of Formula IIb where m is at least 1 and n, R, R¹, R², R³,R⁴, R⁵, Q and Ar¹ are as defined in the Summary of the invention can beprepared from a compound of formula 8, where n is 0, 1 or 2respectively, as illustrated in Scheme B below.

In general, an aminoalkyl derivative of Formula IIb is prepared byreacting a compound of formula 8 with a compound of formula 4 or 5 (seeScheme A) to give an N-protected aminoalkyl derivative of formula 9,followed by removal of the amino protecting group. The conversion of acompound of formula 8 to a compound of Formula IIb is carried out underthe reaction conditions described in method (a) of Scheme A above.

Compounds of formula 8 where n is 0, 1 or 2 can be prepared fromsuitably N-protected pyrrolidinones, piperidinones or4-keto-octahydroazepines respectively, by known procedures. Someexamples of such procedures are described below:

-   -   (i) Compounds of formula 8 where n is 0 or 1 and Q is an        alkylene chain are prepared by reacting a suitably        N-protected-3-pyrrolidinone or N-protected-4-piperidinone        respectively, with a Wittig reagent Br⁻(Ph)₃P⁺-alkylene-Ar¹ to        give an alkene intermediate. Reduction of the olefinic bond,        followed by removal of the N-protecting group then provides        compounds of formula 8.

4-Hydroxypiperidines, 3-pyrrolidinols, 3-pyrrolidinones and4-piperidinones are commercially available. 4-keto-octahydroazepine canbe prepared from 2,4-diketo-N-benzylhexahydroazepine ((see Hong Hu G.and Erik Jagdmann Jr., Tet. Lett., 36(21), 3659-62 (1995)) by knownprocedures.

Detailed descriptions of the synthesis of compounds of Formula IIb bythis method are given in Examples 3 and 4.

Preparation of Compounds of Formula IIc

A compound of Formula IIc where m is 0 or 1, R³ is hydrogen and n, R,R¹, R², R⁴, R⁵, Q and Ar¹ are as defined in the Summary of the inventioncan be prepared from a compound of formula 14 or 10 respectively, asillustrated in Scheme C below.

A compound of Formula IIc where m is 1 can be prepared, as shown inmethod (a), by reacting a compound of formula 10 with a phosphonateylide of formula 11 under Wittig reaction conditions, i.e., in thepresence of a strong non-nucleophilic base (e.g., sodium hydride, sodiumamide, and the like) and in a suitable aprotic organic solvent (e.g.,tetrahydrofuran and the like) to give an α,β-unsaturated ester offormula 12. The (α,β-unsaturated ester 12 is converted to thecorresponding alcohol derivative 13a (m=1) by first converting 12 to analdehyde, followed by treatment with an organometallic reagent such as aGrignard reagent or an organolithium reagent of formula R⁴MgBr or R⁴Li,respectively. The double bond is reduced under hydrogenation reactionconditions and the ester group is reduced to the aldehyde group with asuitable reducing agent such as DIBAL-H®. The alcohol 13a is thenconverted to a compound of Formula IIc by oxidation of the alcohol groupto the ketone group, followed by treatment with an amine of formulaNH(R⁵) under reductive amination reaction conditions. The oxidationreaction is carried in with a suitable oxidizing reagents such aspyridinium dichromate in an aprotic solvent such as dimethylformamideand the like.

A compound of Formula IIc where m is 0 can be prepared, as shown inmethod (b) from a compound of formula 14, by converting 14 to thecorresponding alcohol derivative 13b (m=0) by reduction of the estergroup to the aldehyde followed by treatment with a suitableorganometallic reagent. Compound 13b is then converted to a compound ofIIc where m is 0 by carrying out the oxidation and reductive aminationsteps, utilizing the reaction conditions described above. Compounds ofFormula IIc where m is 0 can also be prepared by the proceduresdescribed in PCT application Publication No. WO 92/12128.

Compounds of formula 10 where n is 0, 1 or 2 are be prepared byN-alkylating a 3-pyrrolidone, a 4-piperidone or a4-keto-octahydroazepine respectively, with a compound of formula Ar¹—Q—Ywhere Y is a leaving group under alkylating conditions as described inmethod (a) (2) of Scheme A.

Compounds of formula 14 (n=1) are prepared by N-alkylating an ethylisonipecotate with a compound of formula Ar¹—Q—Y where Y is a leavinggroup under alkylating conditions as described in method (a) of SchemeA.

Detailed descriptions of the synthesis of a compound of Formula IIcwhere m is 0 or 1 is given in Examples 9 and 10 respectively.

Preparation of Compounds of Formula IId and IIe

A carboxyalkyl derivative of Formula IId (U═N) and IIe (U═C) where m, n,R¹, R², R³, R⁴, Q and Ar¹ are as defined in the Summary of the inventioncan be prepared from a compound of formula 1 or 8 respectively, asillustrated in Scheme D below.

A carboxy derivative of Formula IId or IIe is prepared, as shown above,by reacting a compound of formula 1 or 8 with an alkylating agent offormula 15 where Y is halo or sulfonyloxy group, followed by hydrolysisof the ester group. The alkylation reaction is carried under thereaction conditions described previously ((see scheme A method (a)). Thehydrolysis of the ester group is carried out in the presence of anaqueous base (e.g., sodium hydroxide, lithium hydroxide, and the like)in an alcoholic organic solvent such as methanol, ethanol, and the like.The reaction proceeds either at ambient temperature or upon heating.Alternatively, a carboxyethyl derivative of Formula IId or IIe where R³is hydrogen is prepared by reacting a compound of formula 1 or 8 with anα,β-unsaturated ester of formula 16 under Michael addition reactionconditions i.e., in the presence of a suitable base such as methoxideand in a protic organic solvent (e.g., methanol, ethanol and the like)to give a 3-propionate derivative of formula 17a or 17b, respectively.Hydrolysis of the ester group in 17a or 17b then provides thecorresponding carboxyethyl derivative of Formula IId or IIerespectively, where R³ is hydrogen.

Compounds of formula 1 or 8 are prepared as described previously inSchemes A and B respectively. Compounds of formula 15 and 16 are eithercommercially available or can be prepared by methods known in the art.For example, halo acids and α,β-unsaturated ester such as methyl2-bromo-2-methylpropionate, methyl 2-bromopropionate, methyl3-bromo-2-methylpropionate, methyl α-bromophenylacetate, methylmethacrylate are commercially available. A detailed description of thesynthesis of a carboxyethylpiperazine of Formula IId by this method isgiven in Example 6.

Preparation of Compounds of Formula IIf

A carboxyalkyl derivative of Formula IIf where n, m, R¹, R², R³, R⁴, Qand Ar¹ are as defined in the Summary of the invention can be preparedfrom a compound of formula 17 or 18 respectively, as illustrated inScheme E below.

A carboxyalkyl derivative of Formula IIf can be prepared by reacting acompound of formula 10 or 18 with a Wittig reagent of formulaBr-(Ph₃P)(CHR)_(m)CR³R⁴CO₂Et, followed by reduction of the double bondand hydrolysis of the ester group to the acid in the resultingunsaturated ester 19, as described previously. Alternatively, compoundsof Formula IIf can be prepared from 18 (where R is hydrogen or alkyl) byfollowing the reaction procedures described for the synthesis ofcompound 4 where X is carboxy in Scheme A, method (a).

Compounds of formula 18 can be prepared from compounds of formula 14 bymethods well known in the art.

Compounds of Formula II(d-f) are used for the synthesis of compound ofFormula (I) where E is an inverse amide i.e., —N(R⁶)CO—.

Synthesis of Compounds of Formula (I) from Compounds of Formulae II(a-f)

Compounds of Formula (I) are prepared from compounds of Formulae II(a-f)as described in Schemes F-J below.

Compounds of Formula (I) where E is —C(O)N(R⁵)— are prepared asdescribed in Scheme F below:

A compound of Formula (I) where E is an amide group can be prepared,either:

-   -   (i) by reacting a compound of Formula II(a-c) with an acylating        reagent Ar—F—C(O)L, where L is a leaving group under acylating        conditions, such as a halo (particularly Cl or Br) or        imidazolide. Suitable solvents for the reaction include aprotic        polar solvents (e.g., dichloromethane, THF, dioxane and the        like). When an acyl halide is used as the acylating agent the        reaction is carried out in the presence of a non-nucleophilic        organic base (e.g., triethylamine or pyridine, preferably        pyridine); or    -   (ii) by heating a compound of Formula II (a-c) with an acid        anhydride. Suitable solvents for the reaction are        tetrahydrofuran, dioxane and the like. Detailed descriptions of        the conversion of a compound of Formula IIa and IIb to compounds        of Formula (I) where n is 1 and E is —C(O)NH— is given in        Examples 1, 3, 4, 5 and 10.

Compounds of Formula (I) where E is —N(R⁶)C(O)N(R⁵)— or —N(R⁶)C(S)N(R⁵)—are prepared as described in Scheme G below:

A compound of Formula (I) where E is a urea/thiourea group can beprepared, either:

-   -   (i) by reacting a compound of Formula II(a-c) with an activating        agent such as carbonyl diimidazole/thiocarbonyl diimidazole,        followed by nucleophilic displacement of the imidazole group        with a primary or secondary amine. The reaction occurs at        ambient temperature. Suitable solvents include polar organic        solvents (e.g., tetrahydrofaran, dioxane and the like);    -   (ii) by reacting a compound of Formula II (a-c) with a        carbamoyl/thiocarbamoyl halide. The reaction is carried out in        the presence of a non-nucleophilic organic base. Suitable        solvents for the reaction are dichloromethane,        1,2-dichloroethane, tetrahydrofuran or pyridine; or    -   (iii) by reacting a compound of formula II (a-c) with an        isocyanate/isothiocyanate in an aprotic organic solvent (e.g.,        benzene, tetrahydrofuran, dimethylformamide and the like).

Detailed descriptions of the conversion of a compound of Formula IIa toa compound of Formula (I) where n is 1 and E is —NHC(O)NH— or—N(R⁶)C(S)N(R⁵)— is given in Examples 2 and 8. A detailed description ofthe conversion of a compound of Formula IIc where m is 0 to a compoundof Formula (I) where E is —NHC(O)NH— is given in Example 9.

Compounds of Formula (I) where E is —SO₂N(R⁵)— are prepared as describedin Scheme H below:

A compound of Formula (I) where E is a sulfonamido group can be preparedby reacting a compound of Formula II(a-c) with a sulfonyl halide,utilizing the reaction conditions described in method (i) of Scheme F.Sulfonyl halides are commercially available or may be prepared bymethods such as those described in (1) Langer, R. F.; Can. J. Chem. 61,1583-1592, (1983); (2) Aveta, R.; et. al.; Gazetta Chimica Italiana,116, 649-652, (1986); (3) King, J. F. and Hillhouse, J. H.; Can. J.Chem.; 54, 498, (1976); and (4) Szymonifka, M. J. and Heck, J. V.; Tet.Lett.; 30, 2869-2872, (1989).

A detailed description of the conversion of a compound of Formula IIa toa compound of Formula (I) where n is 1 and E is —N(R⁶)SO₂— is given inExample 7.

Compounds of Formula (I) where E is —N(R⁶)SO₂N(R⁵)— are prepared asdescribed in Scheme I below:

A compound of Formula (I) where E is a sulfamide group can be preparedby reacting a compound of Formula II (a-c) with a sulfamoyl halide,utilizing the reaction conditions described in method (i) of Scheme E.Sulfamoyl halides are commercially available or may be prepared bymethods such as those described in Graf, R; German Patent, 931225 (1952)and Catt, J. D. and Matler, W. L; J. Org. Chem., 39, 566-568, (1974).

Compounds of Formula (I) where E is —N(R⁶)C(O)— are prepared asdescribed in Scheme J below:

A compound of Formula (I) where E is an inverse amide can be prepared byreacting a compound of Formula II(d-f) with an amine in the presence ofa suitable coupling agent (e.g., N,N-dicyclohexylcarbodiimide,1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, and the like) in asuitable organic solvent such as methylene chloride, tetrahydrofuran,dimethylformamide and the like. A detailed description of a compound ofFormula IId to a compound of Formula I where n is 1 and E is —NHC(O)— isgiven in Example 6.

Utility, Testing and Administration General Utility

The compounds of the invention are CCR-3 receptor antagonists andinhibit eosinophil recruitment by CCR-3 chemokines such as RANTES,eotaxin, MCP-2, MCP-3 and MCP-4. Compounds of this invention andcompositions containing them are useful in the treatment ofeosiniphil-induced diseases such as inflammatory or allergic diseasesand including respiratory allergic diseases such as asthma, allergicrhinitis, hypersensitivity lung diseases, hypersensitivity pneumonitis,eosinophilic pneumonias (e.g., chronic eosinophilic pneumonia);inflammatory bowel diseases (e.g., Crohn's disease and ulcerativecolitis); and psoriasis and inflammatory dermatoses such as dermatitisand eczema.

Testing

The CCR-3 antagonistic activity of the compounds of this invention wasmeasured by in vitro assays such as ligand binding and chemotaxis assaysas described in more detail in Examples 15, 16 and 17. In vivo activitywas assayed in the Ovalbumin induced Asthma in Balb/c Mice Model asdescribed in more detail in Example 18.

Administration and Pharmaceutical Composition

In general, the compounds of this invention will be administered in atherapeutically effective amount by any of the accepted modes ofadministration for agents that serve similar utilities. The actualamount of the compound of this invention, i.e., the active ingredient,will depend upon numerous factors such as the severity of the disease tobe treated, the age and relative health of the subject, the potency ofthe compound used, the route and form of administration, and otherfactors.

Therapeutically effective amounts of compounds of Formula (I) may rangefrom approximately 0.05-20 mg per kilogram body weight of the recipientper day; preferably about 0.1-10 mg/kg/day. Thus, for administration toa 70 kg person, the dosage range would most preferably be about 7 mg to0.7 g per day.

In general, compounds of this invention will be administered aspharmaceutical compositions by any one of the following routes: oral,inhalation (e.g., intranasal or oral inhalation) or parenteral (e.g.,intramuscular, intravenous or subcutaneous) administration. A preferredmanner of administration is oral using a convenient daily dosage regimenwhich can be adjusted according to the degree of affliction.Compositions can take the form of tablets, pills, capsules, semisolids,powders, sustained release formulations, solutions, suspensions,elixirs, or any other appropriate compositions. Another preferred mannerfor administering compounds of this invention is inhalation. This is aneffective means for delivering a therapeutic agent directly to therespiratory tract for the treatment of diseases such as asthma and othersimilar or related respiratory tract disorders (see U.S. Pat. No.5,607,915).

The choice of formulation depends on various factors such as the mode ofdrug administration and the bioavailability of the drug substance. Fordelivery via inhalation the compound can be formulated as liquidsolutions or suspensions, aerosol propellants or dry powder and loadedinto a suitable dispenser for administration. There are three types ofpharmaceutical inhalation devices—nebulizer inhalers, metered-doseinhalers (MDI) and dry powder inhalers (DPI). Nebulizer devices producea stream of high velocity air that causes the therapeutic agents (whichhas been formulated in a liquid form) to spray as a mist which iscarried into the patient's respiratory tract. MDI's typically have theformulation packaged with a compressed gas. Upon actuation, the devicedischarges a measured amount of therapeutic agent by compressed gas,thus affording a reliable method of administering a set amount of agent.DPI's administer therapeutic agents in the form of a free flowing powderthat can be dispersed in the patient's inspiratory air-stream duringbreathing by the device. In order to achieve a free flowing powder, thetherapeutic agent is formulated with an excipient, such as lactose. Ameasured amount of the therapeutic is stored in a capsule form and isdispensed to the patient with each actuation.

Recently, pharmaceutical formulations have been developed especially fordrugs that show poor bioavailability based upon the principle thatbioavailability can be increased by increasing the surface area i.e.,decreasing particle size. For example, U.S. Pat. No. 4,107,288 describesa pharmaceutical formulation having particles in the size range from 10to 1,000 nm in which the active material is supported on a crosslinkedmatrix of macromolecules. U.S. Pat. No. 5,145,684 describes theproduction of a pharmaceutical formulation in which the drug substanceis pulverized to nanoparticles (average particle size of 400 nm) in thepresence of a surface modifier and then dispersed in a liquid medium togive a pharmaceutical formulation that exhibits remarkably highbioavailability.

The compositions are comprised of in general, a compound of Formula (I)in combination with at least one pharmaceutically acceptable excipient.Acceptable excipients are non-toxic, aid administration, and do notadversely affect the therapeutic benefit of the compound of Formula (I).Such excipient may be any solid, liquid, semi-solid or, in the case ofan aerosol composition, gaseous excipient that is generally available toone of skill in the art.

Solid pharmaceutical excipients include starch, cellulose, talc,glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silicagel, magnesium stearate, sodium stearate, glycerol monostearate, sodiumchloride, dried skim milk and the like. Liquid and semisolid excipientsmay be selected from glycerol, propylene glycol, water, ethanol andvarious oils, including those of petroleum, animal, vegetable orsynthetic origin, e.g., peanut oil, soybean oil, mineral oil, sesameoil, etc. Preferred liquid carriers, particularly for injectablesolutions, include water, saline, aqueous dextrose, and glycols.

Compressed gases may be used to disperse a compound of this invention inaerosol form. Inert gases suitable for this purpose are nitrogen, carbondioxide, etc.

Other suitable pharmaceutical excipients and their formulations aredescribed in Remington's Pharmaceutical Sciences, edited by E. W. Martin(Mack Publishing Company, 18th ed., 1990).

The level of the compound in a formulation can vary within the fullrange employed by those skilled in the art. Typically, the formulationwill contain, on a weight percent (wt %) basis, from about 0.01-99.99 wt% of a compound of Formula (I) based on the total formulation, with thebalance being one or more suitable pharmaceutical excipients.Preferably, the compound is present at a level of about 1-80 wt %.Representative pharmaceutical formulations containing a compound ofFormula (I) are described in Example 14.

EXAMPLES

The following preparations and examples are given to enable thoseskilled in the art to more clearly understand and to practice thepresent invention. They should not be considered as limiting the scopeof the invention, but merely as being illustrative and representativethereof.

Synthetic Examples Example 1 Synthesis ofN-{1(S)-[4-(3,4-Dichlorobenzyl)piperazin-1-ylmethyl]-2-methylpropyl}-4-methylbenzanidedihydrochloride salt

Step 1

3,4-Dichlorobenzyl bromide (35.20 g, 150 mmol) was added to a solutionof N-(tert-butoxycarbonyl)piperazine (24.84 g, 130 mmol) andtriethylamine (20.91 ml, 150 mmol) in chloroform (100 ml) over 30 min.After 1 h, the reaction mixture was diluted with ethyl acetate and theproduct was precipitated out as the hydrochloride salt by adding 1Naqueous hydrogen chloride solution. The solid product was filtered,washed with water and then resuspended in ethyl acetate. Two equivalentsof 1N aqueous sodium hydroxide solution was added and the free amine wasextracted into ethyl acetate. The organic layer was separated, driedover magnesium sulfate, filtered and concentrated to provide1-(tert-butoxycarbonyl)-4-(3,4-dichlorobenzyl)piperazine (45 g).

Step 2

Trifluoroacetic acid (75 ml, 974 mmol) was added to a solution1-(tert-butoxycarbonyl)-4-(3,4-dichlorobenzyl)piperazine (45 g, 130mmol) in chloroform (75 ml). The reaction mixture was stirred for 1 h atroom temperature and then made basic with a sodium hydroxide solution.The product was extracted into ethyl acetate and the organic layer waswashed with sodium bicarbonate solution, dried over magnesium sulfateand concentrated in vacuo to give 1-(3,4-dichlorobenzyl)piperazine (35.8g) as a solid.

Step 3

1-(3-Dimethylaminopropyl3-ethylcarbodiimide hydrochloride (5.08 g, 26.5mmol) was added to a solution of 1-(3,4-dichlorobenzyl)piperazine (5 g,20.4 mmol) and L-Boc-valine (5.76 g, 26.5 mmol) in methylene chloride.After 2 h, the product was extracted into ethyl acetate. The organiclayer was washed with sodium bicarbonate solution, dried over magnesiumsulfate, filtered and concentrated in vacuo. Column chromatography withhexanes/ethyl acetate (1:1) as the eluant gave1-(S)-[4-(3,4-dichlorobenzyl)piperazin-1-ylcarbonyl]-N-(tert-butoxycarbonyl)-2-methylpropylamine(5.46 g) as a foam.

Step 4

1 N ethereal hydrogen chloride solution (80 ml, 80 mmol) was added to asolution of1(S)-[4-(3,4-dichlorobenzyl)piperazin-1-ylcarbonyl]-N-(tert-butoxycarbonyl)-2-methylpropylamine(4.28 g, 9.64 mmol) in methanol (50 ml) and the reaction mixture washeated at 70° C. After 2.5 h, the reaction mixture was concentrated andthe solid was suspended in ether and filtered to give1-(S)-[4-(3,4-dichlorobenzyl)piperazin-1-ylcarbonyl]-2-methylpropylamine as the bis hydrochloride salt. The productwas dissolved in water, treated with triethylamine (4.0 ml, 28.9 mmol)and the free amine was extracted into ethyl acetate. The ethyl acetatelayer was dried over magnesium sulfate, filtered and concentrated togive1-(S)-[4-(3,4-dichlorobenzyl)piperazin-1-ylcarbonyl]-2-methylpropylamine(3.2 g) as the free amine.

Step 5

A 1.0 M diborane solution in tetrahydrofuran (65.2 ml, 65.2 mmol) wasadded to a solution of1-(S)-[4-(3,4-dichlorobenzyl)piperazin-1-ylcarbonyl]-2-methylpropylamine(3.2 g, 9.3 mmol) in tetrahydrofuran (15 ml). The mixture was heated atreflux under nitrogen atmosphere for 2 h and then concentrated in vacuo.The residue was dissolved in methanol, acidified with 6 N hydrogenchloride solution (50 ml) and then reheated to 70° C. After heating for1 h, the reaction mixture was cooled and basified with a sodiumhydroxide solution and the product was extracted into ethyl acetate. Theethyl acetate layer was washed with sodium bicarbonate solution, driedover magnesium sulfate, filtered and concentrated to provide1-(S)-[4-(3,4-dichlorobenzyl)piperazin-1-ylmethyl]-2-methylpropylamine(3.53 g) as an oil.

Step 6

p-Toluoyl chloride (0.48 ml, 3.63 mmol) was added to a solution of1(S)-[4-(3,4-dichlorobenzyl)piperazin-1-ylmethyl]-2-methylpropylamine (1g, 3.0 mmol) and triethylamine (0.633 ml, 4.54 mmol) in methylenechloride under nitrogen atmosphere. After 1 h, the product was extractedinto ethyl acetate and the organic layer was washed with sodiumbicarbonate solution, dried over magnesium sulfate, filtered andconcentrated in vacuo. Column chromatography with hexanes/ethyl acetate(1:2) gaveN-{1(S)-[4-(3,4-dichlorobenzyl)piperazin-1-ylmethyl]-2-methylpropyl}-4-methylbenzamide(1.2 g) as an oil. The free amine was dissolved in ether and 3.5equivalents of 1N ethereal HCl solution (10.7 ml) was added. Filtrationof the resulting solid providedN-{1(S)-[4-(3,4-dichlorobenzyl)piperazin-1-ylmethyl]-2-methylpropyl}-4-methylbenzamide(1.2 g) as the bis hydrochloride salt, mp 227.8-228.9° C.

1. Proceeding as described in Example 1, Steps. 1-4 above butsubstituting L-Boc-valine in Step 3 with DL-Boc-valine gave1-(RS)-[4-(3,4-dichlorobenzyl)piperazin-1-ylcarbonyl]-2-methylpropylaminewhich upon reduction (step 5) and reaction with3,4-methylenedioxybenzoyl chloride (step 6) gaveN-{1(RS)-[4-(3,4-dichlorobenzyl)-piperazin-1-ylmethyl]-2-methylpropyl}-3,4-methylenedioxybenzamide.

2. Proceeding as described in Example 1, Steps 1-4 above butsubstituting L-Boc-valine in Step 3 with L-Boc-tert-leucine(commercially available from Fluka) gave1-(S)-[4-(3,4-dichlorobenzyl)piperazin-1-ylcarbonyl]-2,2-dimethylpropylaminewhich was reduced to1-(S)-[4-(3,4-dichloro-benzyl)piperazin-1-ylmethyl]-2,2-methylpropylamine(Step 5) and then reacted with:

-   -   4-Methylsulfonylbenzoyl chloride;    -   4-Acetoxybenzoyl chloride;    -   4-N,N-Dimethylaminobenzoyl chloride;    -   5-Methyl-2-thenoyl chloride; and    -   4-Methylbenzoyl chloride, to give    -   N-{1(S)-[4-(3,4-Dichlorobenzyl)piperazin-1-ylmethyl]-2,2-dimethylpropyl}-4-methylsulfonylbenzamide        dihydrochloride salt, mp 190-191° C.;    -   N-{1(S)-[4-(3,4-Dichlorobenzyl)piperazin-1-ylmethyl]-2,2-dimethylpropyl}-4-acetoxybenzamide        dihydrochloride salt, mp 241-242° C.;    -   N-{1(S)-[4-(3,4-Dichlorobenzyl)piperazin-1-ylmethyl]-2,2-dimethylpropyl}-4-N,N-dimethylaminobenzamide        dihydrochloride salt, mp 101.5-105° C.;    -   N-{1(S)-[4-(3,4-Dichlorobenzyl)piperazin-1-ylmethyl]-2,2-dimethylpropyl}-5-methyl-2-thiophenecarboxamide        dihydrochloride salt, mp 249-253° C.; and    -   N-{1(S)-[4-(3,4-Dichlorobenzyl)piperazin-1-ylmethyl]-2,2-dimethylpropyl}-4-methylbenzamide        dihydrochloride salt by following the procedure described in        Steps 5 and 6 above.

3. Proceeding as described in Example 1, Steps 1-4 above butsubstituting L-Boc-valine in Step 3 with DL-Boc-tert-leucine gave1-(RS)-[4-(3,4-dichlorobenzyl)-piperazin-1-ylcarbonyl]-2,2-methylpropylaminewhich was reduced to1-(RS)-[4-(3,4-dichlorobenzyl)piperazin-1-ylmethyl]-2,2-methylpropylamine(Step 5) and reacted with:

-   -   3-Cyanobenzoyl chloride; and    -   3,4-Difluorobenzoyl chloride, to give    -   N-{1(RS)-[4-(3,4-Dichlorobenzyl)piperazin-1-ylmethyl]-2,2-dimethylpropyl}-3-cyanobenzamide;        and;    -   N-{1(RS)-[4-(3,4-Dichlorobenzyl)piperazin-1-ylmethyl]-2,2-dimethylpropyl}-3,4-difluorobenzamide,        respectively.

4. Proceeding as described in Example 1, but substitutingN-(tert-butoxycarbonyl)-piperazine in Step 1 with3-methyl-N-(tert-butoxycarbonyl)piperazine and L-Boc-valine in Step 3with DL-Boc-valine gaveN-{1(RS)-[3-methyl-4-(3,4-dichlorobenzyl)piperazin-1-ylmethyl]-2-methylpropyl}-4-methylbenzamidedihydrochloride salt.

Example 2 Synthesis of1-{2-[4-(3,4-Dichlorobenzyl)-piperazin-1-yl]cyclohexyl}-3-(3-methoxyphenyl)urea

Step 1

A mixture of 1-nitrocyclohexene (311 mg, 2.45 mmol),dichlorobenzylpiperazine [prepared as described in Example 1](600 mg,2.45 mmol), and triethylamine (512 μl, 3.68 mmol) in methylene chloride(10 ml) was stirred at room temperature under nitrogen atmosphere for 17h. The reaction mixture was diluted with ethyl acetate, washed with anaqueous sodium bicarbonate solution, dried over magnesium sulfate andconcentrated in vacuo. The residue was chromatographed withhexanes/ethyl acetate (2:1) as the eluant to provide1-(3,4-dichlorobenzyl)-4-(2-nitrocyclohexyl)piperazine (461 mg) as anoil.

Step 2

Platinum (IV) oxide (15 mg, 0.07 mmol) was added to a solution of1-(3,4-dichlorobenzyl)-4-(2-nitrocyclohexyl)piperazine (187 mg, 0.50mmol) in glacial acetic acid (5 ml). The reaction mixture was stirredunder hydrogen atmosphere at room temperature for 16 h. The reactionmixture was then filtered through a pad of celite. The filtrate was madebasic with a 15% sodium hydroxide solution and the product was extractedinto ethyl acetate. The organic layer was dried over magnesium sulfate,filtered and concentrated in vacuo to provide1-(3,4-dichlorobenzyl)-4-(2-aminocyclohexyl)-piperazine (119 mg) as anoil.

Step 3

A solution of 1-(3,4-dichlorobenzyl)-4-(2-aminocyclohexyl)piperazine(100 mg, 0.29 mmol) and 3-methoxyphenyl isocyanate (38 μl, 0.29 mmol) inmethylene chloride (5 ml) was stirred at room temperature. After 17 h,the product was extracted into ethyl acetate, washed with a bicarbonatesolution, dried over magnesium sulfate and concentrated in vacuo. Columnchromatography with methylene chloride/methanol (97:3) as the eluantgave1-{2-[4-(3,4-dichlorobenzyl)piperazin-1-yl]cyclohexyl}-3-(3-methoxyphenyl)urea(64 mg) as an oil consisting of the trans diastereomer.

Example 3 Synthesis ofN-{1-(S)-[4-(3,4-Dichlorobenzyl)piperidin-1-ylmethyl]-2-methylpropyl}-4-methylbenzamide

Step 1

n-Butyllithium (43.2 ml, 2M in pentane, 108 mmol) was slowly added to anice-cooled suspension of 3,4-dichlorobenzyl triphenylphosphonium bromide(54 g, 108 mmol) (prepared by stirring equimolar amounts of 3,4dichlorobenzyl bromide and triphenylphosphine in THF at 65° overnight)in dry THF (500 ml) under an argon atmosphere. After 15 min., thereaction mixture was allowed to warm to room temperature, and wasstirred for an additional 2 h. 1-tert-butoxycarbonyl-4-piperidone (21.42g, 108 mmol) was added and the stirring was continued overnight. Hexane(21) was added and the reaction was stirred and then filtered. Thefiltrate was concentrated in vacuo to give 41.8 g of an orange gum.Column chromatography on 0.5 kg flash grade silica, eluting with agradient of 70% methylene chloride/hexane through 100% methylenechloride, followed by a gradient of 1% methanol/methylene chloridethrough 5% methanol/methylene chloride gave1-(tert-butoxycarbonyl)-4-(3,4-dichlorobenzylidene)piperidine (29 g) asa light tan oil.

Step 2

Platinum oxide (0.3 g) was added to a solution of1-(tert-butoxycarbonyl)-4-(3,4-dichlorobenzylidene)piperidine (29 g,84.7 mmol) in ethyl acetate (500 ml) and the mixture was stirred under ahydrogen atmosphere overnight. The reaction mixture was filtered throughcelite and the filtrate was concentrated to give1-(tert-butoxycarbonyl)-4-(3,4-dichlorobenzyl)piperidine (30 g) as a tanoil.

Step 3

Trifluoroacetic acid (50 ml) was added to a solution of1-(tert-butoxycarbonyl)-4-(3,4-dichlorobenzyl)piperidine (24 g, 69.7mmol) in methylene chloride (150 ml) and the reaction mixture wasstirred for 1 h. The solvent was removed under reduced pressure,followed by addition of ethyl acetate (200 ml), and the resultingmixture was made basic with 1N aqueous sodium hydroxide. The organiclayer was separated, dried over magnesium sulfate and the solvent wasremoved under reduced pressure to give 4-(3,4-dichlorobenzyl)piperidine(17.1 g) as light brown solid.

Step 4

L-BOC-Valine (1.3 g, 5.98 mmol) and1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (1.15 g, 5.98 mmol) wereadded to a solution of 4-(3,4-dichlorobenzyl)piperidine (1.12 g, 4.57mmol) in methylene chloride (15 ml) and the reaction mixture was stirredat room temperature under an argon atmosphere. After 3 h the solventswere removed under vacuo and water (10 ml) and ethyl acetate (25 ml)were added. The organic layer was separated, dried over magnesiumsulfate and concentrated under reduced pressure. Column chromatographywith 15-20% ethyl acetate/hexane as the eluant gave1-(S)-[4-(3,4-dichlorobenzyl)-piperidin-1-ylcarbonyl]-N-(tert-butoxycarbonyl)-2-methylpropylamine(1.89 g) as a gummy foam.

Step 5

To a solution of1-(S)-[4-(3,4-dichlorobenzyl)piperidin-1-ylcarbonyl]-N-(tert-butoxycarbonyl)-2-methylpropylamine(5.9 g, 13.2 mmol) in methylene chloride (100 ml) was addedtrifluoroacetic acid (30 ml) at room temperature. After 4 h, thereaction mixture was concentrated and the residue was stirred with ethylacetate (200 ml) and water (100 ml) while adjusting the pH to 8 with 15%aqueous sodium hydroxide solution. The organic layer was separated andthe aqueous layer was extracted twice with ethyl acetate. The combinedorganic portions were dried over magnesium sulfate, filtered andconcentrated in vacuo to give1-(S)-[4-(3,4-dichlorobenzyl)piperidin-1-ylcarbonyl-2-methylpropylamine(4.53 g) as a colorless gum.

Step 6

To a solution of1-(S)-[4-(3,4-dichlorobenzyl)piperidin-1-ylcarbonyl-2-methylpropylamine(4.53 g, 13.3 mmol) in dry tetrahydrofuran (100 ml) was added diborane(92.4 ml, 92.4 mmol, 1 M in THF) and the reaction mixture was stirredunder argon at 65° C. After 3 h, the reaction mixture was cooled in anice bath and aqueous hydrochloric acid (60 ml, 6 N) was slowly addedwith stirring. The reaction mixture was concentrated on a rotovap andthe aqueous solution was stirred at 100° C. After 1 h, the reactionmixture was cooled to 0° C. and potassium hydroxide pellets were slowlyadded until pH 8 was obtained. The solution was extracted twice withethyl acetate (100 ml), dried over magnesium sulfate and concentrated invacuo. The colorless liquid (3.84 g) was flash chromatographed, elutingwith 2.5-10% MeOH/CH₂Cl₂ containing 1% NH₄OH. The free amine wasdissolved in anhydrous ether and ethereal HCl was added to afford1-(S)-[4-(3,4-dichlorobenzyl)piperidin-1-ylmethyl]-2-methylpropylamineas the HCl salt.

Step 7

p-Toluoyl chloride (0.14 ml, 1 mmol) was added to a solution of1-(S)-[4-(3,4-dichlorobenzyl)piperidin-1-ylmethyl]-2-methylpropylamine(0.33 g, 1 mmol) in dry pyridine (7 ml) at 0° C. under argon atmosphere.The solution was stirred for 30 min., at 0° C. and then allowed to warmto room temperature. After 3 h, the reaction mixture was concentratedunder reduced pressure and water (10 ml) was added. The product wasextracted with ethyl acetate and the organic layer was dried withmagnesium sulfate and then concentrated in vacuo. The crude product (0.5g) was chromatographed by eluting with a gradient of from 1% to 4%methanol/methylene chloride to giveN-{1-(S)-[4-(3,4-dichlorobenzyl)piperidin-1-ylmethyl]-2-methylpropyl}-4-methylbenzamide(0.25 g) as partially solidified gum.

Example 4N-{1-(RS)-[4-(4-Amino-5-chloro-2-methoxyphenylcarbonylaminomethyl)piperidin-1-yl-methyl]-2-methylpropyl}-4-methylbenzamide

Step 1

Diisopropylethyl amine (17.4 ml, 134 mmol) was added a solution of(DL)-valinol (9.85 g, 95 mmol) in methylene chloride (100 ml). Thereaction mixture was cooled to 0° C., treated with a solution ofp-toluoyl chloride (12.8 ml, 91 mmol ) in methylene chloride (50 ml) andthen allowed to warm to room temperature. After stirring for 3 hours,excess aqueous sodium hydroxide solution was added and the reaction wastransferred to a separatory funnel. The organic layer was separated andthe aqueous layer washed with one portion of methylene chloride. Thecombined organic layers were washed with water and brine, dried overmagnesium sulfate and concentrated in vacuo. Chromatography eluting with25% ethyl acetate in hexanes, followed by 50% ethyl acetate in hexanesgave N-p-toluoyl valinol (18.04 g).

Step 2

Dimethylsulfoxide (2.2 ml, 31 mmol ) was slowly added via syringe to astirred −78° C. solution of oxalyl chloride (15 ml, 171 mmol) inmethylene chloride (35 ml) under inert atmosphere. After 10 min., asolution of N-p-toluoyl valinol (6.0 g, 29 mmol) in methylene chloride(50 ml) was added and the stirring was continued for additional 15 min.Triethylamine was added (6 ml, 389 mmol) and the reaction was allowed towarm to ambient temperature. After 1.5 h, the reaction was diluted with50% ethyl acetate in hexanes and washed with water and brine. Filtrationthrough a pad of silica gel and subsequent solvent removal left a solidresidue. Chromatography eluting with 20% ethyl acetate in hexanes, then33% ethyl acetate in hexanes gave N-p-toluoyl valinaldehyde (3.6 g) as asolid, which was utilized in Step 6.

Step 3

tert-Butyloxycarbonyl anhydride (6.69 g, 30.6 mmol) was added to asolution of 4-(aminomethyl)piperidine (7 g, 61.3 mmol) in chloroform (40ml) at 0° C. The reaction mixture was allowed to warm to roomtemperature over 3 h and then stirred an additional 15 h. The reactionmixture was washed with water, the organic layer was separated and driedover magnesium sulfate, filtered and concentrated to provideN-tert-butyloxy-carbonyl-4-(aminomethyl)piperidine (6.55 g) as a paleyellow oil.

Step 4

1,1′-Carbonyldiimidazole (1.61 g, 9.91 mmol) was added to a solution of4-amino-5-chloro-2-methoxybenzoic acid (2.0 g, 9.91 mmol) indimethylformamide (5 ml). After stirring for 5 min. at room temperature,solution of N-tert-butyloxycarbonyl-4-(aminomethyl)piperidine (1.77 g,8.26 mmol) in dimethylformamide (5 ml) was added and the reactionmixture was heated at 55° C. After 23 h, the product was extracted intoethyl acetate and the organic layer was washed with aqueous sodiumbicarbonate, dried over magnesium sulfate, filtered and concentrated.Flash chromatography of the crude product with 2:1, ethylacetate/hexanes as the eluant gaveN-tert-butyloxycarbonyl-4-(4-amino-5-chloro-2-methoxyphenylcarbonylaminomethyl)piperidine(2.63 g) as a foam.

Step 5

To a solution ofN-tert-butyloxycarbonyl-4-(4-amino-5-chloro-2-methoxyphenyl-carbonylaminomethyl)piperidine(500 mg, 1.26 mmol) in methanol solution (30 ml) was added an ethereal1N hydrogen chloride solution (12.6 ml, 12.6 mmol). The solution washeated at 50° C. The reaction mixture became heterogeneous within 5 min.After 1.5 h, the reaction mixture was concentrated to give a white solidwhich was suspended in diethylether and filtered to give4-(4-amino-5-chloro-2-methoxyphenylcarbonylaminomethyl)piperidine as abis-hydrochloride salt (433 mg).

Step 6

To a heterogeneous mixture of4-(4-amino-5-chloro-2-methoxyphenylcarbonylaminomethyl)piperidine (304mg, 0.82 mmol) and triethylamine (309 μl, 2.21 mmol) in methylenechloride (20 ml) was added aldehyde N-p-toluoyl valinaldehyde (150 mg,0.68 mmol) and sodium triacetoxyborohydride (216 mg, 1.02 mmol) at roomtemperature. After 1 h the reaction mixture was diluted with ethylacetate and washed with sodium bicarbonate solution. The organic layerwas separated, dried over magnesium sulfate and concentrated in vacuo.Flash chromatography of the crude product with 97:3, methylenechloride/methanol as the eluant gaveN-{1(RS)-[4-(4-amino-5-chloro-2-methoxyphenylcarbonyl-aminomethyl)piperidin-1-ylmethyl]-2-methylpropyl}-4-methylbenzamide(139mg) as a foam.

Example 5{1-(4-Methylbenzoyl)-2(R)-[4-(3,4-dichlorobenzyl)piperazin-1-ylmethyl]}-pyrrolidinedihydrochloride salt

Step 1

1-Ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride(1.03 g, 7mmol) was added to a solution of N-BOC-D-Proline (1.51 g, 7 mmol) inmethylene chloride (12 ml) and the reaction mixture was stirred at roomtemperature. After 0.5 h, 3,4-dichlorobenzylpiperazine (1.32 g, 5.4mmol) [prepared as described in Example 1] was added and the stirringwas continued for 16 h. The reaction mixture was then quenched withwater, basified with saturated sodium bicarbonate solution and extractedwith ethyl acetate. The ethyl acetate layer was separated and washedwith brine, dried over magnesium sulfate and concentrated. Flashchromatography with 30% acetone in dichloromethane as the eluant gave2(R)-[4-(3,4-dichlorobenzyl)piperazin-1-ylcarbonyl]}-N-(tert-butoxycarbonyl)pyrrolidine (1.2 g) as an oil.

Step 2

Borane (15.8 ml, 1.0 M solution in THF) was added dropwise to a solutionof2(R)-[4-(3,4-dichlorobenzyl)piperazin-1-ylcarbonyl]}-N-(tert-butoxycarbonyl)pyrrolidine (1.0 g, 2.26 mmol) in tetrahydrofuran (5 ml) was undernitrogen atmosphere and the reaction mixture was heated at reflux. After2 h, the reaction mixture was cooled to room temperature and quenchedwith 6 N hydrochloric acid. The reaction mixture was re-heated at refluxfor another 2 h, cooled to room temperature and then basified with 10%aqueous sodium hydroxide solution. The product was extracted into ethylacetate and the organic layer was separated and washed with brine, driedover magnesium sulfate, and concentrated. Purification with columnchromatography with methylene chloride containing 10% ammonium hydroxidein methanol as the eluant gave2(R)-[4-(3,4-dichlorobenzyl)piperazin-1-ylmethyl]}pyrrolidine (0.62 g)as an oil.

Step 3

Triethylamine (0.19 ml, 1.5 mmol) and p-toluoyl chloride (0.11 ml, 0.84mmol) were added to a solution of2(R)-[4-(3,4-dichlorobenzyl)piperazin-1-ylmethyl]-pyrrolidine (0.25 g,0.76 mmol) in methylene chloride (5 ml). After 1 h, the reaction mixturewas quenched with water and the product was extracted into ethylacetate. The ethyl acetate layer was washed with brine, dried overmagnesium sulfate and concentrated. Preparative TLC with 5% methanol inmethylene chloride afforded{1-(4-methylbenzoyl)-2(R)-[4-(3,4-dichlorobenzyl)piperazin-1-ylmethyl]}pyrrolidine0.245 g of an oil which was converted to its dihydrochloride salt andrecrystallized from a methanolethyl acetate mixture to give{1-(4-methylbenzoyl)-2(R)-[4-(3,4-dichlorobenzyl)-piperazin-1-ylmethyl]}pyrrolidinedihydrochloride (0.18 g) as a white solid; m.p. 249.6-250.1° C.

Example 6 Synthesis of2-(RS)-[4-(3,4-Dichlorobenzyl)piperazin-1-ylmethyl]-N-(4-methylphenyl)propionamide

Step 1

A mixture of 3,4-dichlorobenzylpiperazine (2.47 g, 10.1 mmol), methylmethacrylate (2.2 ml, 21 mmol), and sodium methoxide (49 mg, 0.91 mmol)in methanol (20 ml) was heated to reflux. After 72 h, the reactionmixture was concentrated under reduced pressure to yield pale-yellow oil(3.02 g). Column chromatography on silica gel with ethyl acetate aseluant afforded methyl2-(RS)-[4-(3,4-dichlorobenzyl)piperazin-1-ylmethyl]propionate (1.52 g)as a pale-yellow oil.

Step 2

Methyl 2-[4-(3,4-dichlorobenzyl)piperazin-1-ylmethyl]propionate (470 mg,1.36 mmol) and lithium hydroxide monohydrate (185 mg, 4.41 mmol) weredissolved in water (5 ml) and methanol (15 ml) and stirred at roomtemperature. After 21 h, the solvents were removed under reducedpressure. The resulting residue was taken up in a mixture of methylenechloride and water, and the aqueous layer was made acidic (˜pH 4) with1M HCl. The layers were separated and the aqueous phase was extractedwith several portions of methylene chloride. The combined organic layerswere dried over sodium sulfate and concentrated under reduced pressureto afford 2-(RS)-[4-(3,4-dichlorobenzyl)piperazin-1-ylmethyl]propionicacid (444 mg) as a pale-yellow foam.

Step 3

1-Ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (388 mg,2.02 mmol) was added to a solution of2-[4-(3,4-dichlorobenzyl)piperazin-1-ylmethyl]-propionic acid (609 mg,1.84 mmol) p-toluidine (219 mg, 2.04 mmol) and dimethylaminopyridine (22mg, 0.18 mmol) in methylene chloride (20 ml). After 4 h, the mixture wasdiluted with methylene chloride and washed with water. The organic layerwas separated, dried with sodium sulfate and the solvent removed underreduced pressure to give an orange foam (839 mg). Column chromatographyon silica gel with ethyl acetate as eluant yielded2-[4-(3,4-dichlorobenzyl)piperazin-1-ylmethyl]-N-(4-methylphenyl)propionamide(636 g, 82%) as a white foam. A 1M solution of hydrochloric acid inether (4.2 ml) was added to a solution of this product (593 mg, 1.41mmol) in methanol and the solvent was removed under reduced pressure.The resulting viscous oil was triturated with ether/hexanes to yield2-(RS)-[4-(3,4-dichlorobenzyl)piperazin-1-yl-methyl]-N-(4-methylphenyl)propionamide(245 mg) as the hydrochloride salt, m.p. 256.2-256.7° C.

Example 7N-{1-(R)-[4-(3,4-Dichlorobenzyl)piperazin-1-ylmethyl]-2-methylpropyl}-4-fluorobenzenesulfonamidedihydrochloride salt

Triethylamine (21 ml, 0.15 mmol) and 4-fluorobenzenesulfonyl chloride(29 mg, 0.15 mmol) were added to a solution of1-(R)-[4-(3,4-dichlorobenzyl)piperazin-1-ylmethyl]-2-methylpropylamine(50 mg, 0.15 mmol) [prepared as described in Example 1 above] inmethylene chloride (1.5 ml). The reaction mixture was stirred for 2 h,then concentrated. Purification by flash chromatography with 20:1methylene: methanol as the eluant gaveN-{1-(R)-[4-(3,4-dichlorobenzyl)piperazin-1-ylmethyl]-2-methylpropyl}-4-fluorobenzenesulfonamide(49 mg) as a solid.

Example 81-{1-(RS)-[4-(3,4-Dichlorobenzyl)piperazin-1-ylmethyl]-2-methylpropyl}-3-methoxybenzyl-2-thiourea

3-Methoxybenzyl isothiocyanate (22 mg, 0.12 mmol) was added to asolution of1-(RS)-[4-(3,4-dichlorobenzyl)piperazin-1-ylmethyl]-2-methylpropylamine(40 mg, 0.12 mmol) [prepared as described in Example 1 by substitutingL-N-BOC-valine with DL-N-BOC-valine] in methylene chloride (1.5 ml). Thereaction mixture was stirred for 2 h and then concentrated. Purificationby flash chromatography with 20:1 methylene chloride: methanol as theeluant gave1-{1-(RS)-[4-(3,4-dichlorobenzyl)piperazin-1-ylmethyl]-2-methylpropyl}-3-methoxybenzyl-2-thiourea(18 mg) as a solid.

Example 91-{1(RS)-[1-(3,4-Dichlorobenzyl)piperidin-4-yl]-2-methylpropyl}-3-(3-methoxyphenyl)urea

Step 1

3,4-Dichlorobenzyl bromide (1.83 g, 7.63 mmol) was added to a solutionof ethyl isonipecotate (1 g, 6.36 mmol) and triethylamine (1.33 ml, 9.54mmol) in methylene chloride solution (10 ml) at room temperature. After17 h, the reaction mixture was diluted with ethyl acetate and washedwith aqueous sodium bicarbonate solution (10 ml). The organic layer wasdried over magnesium sulfate, filtered, and concentrated. Flashchromatography with 9:1, hexanes/ethyl acetate followed by 6:1hexanes/ethyl acetate gave ethyl 1-(3,4-dichlorobenzyl)isonipecotate(1.78 g) as a pale yellow oil.

Step 2

A 1.5 M solution of DIBAL-H™ in toluene (1.27 ml, 1.90 mmol) was addeddropwise over 10 min. to a solution of ethyl1-(3,4-dichlorobenzyl)isonipecotate (500 mg, 1.58 mmol) in toluenesolution (5 ml) at −78° C. After 40 min., aqueous sodium bicarbonatesolution was added and the reaction mixture was warmed to roomtemperature. The product was extracted into diethyl ether. The organiclayer was dried over magnesium sulfate, filtered and concentrated toprovide 1-(3,4-dichlorobenzyl)-4-formylpyridine (430 mg) as an oil.

Step 3

Isopropylmagnesium chloride in tetrahydrofuran (3.7 ml, 7.35 mmol, 2.0M) was added to a solution of 1-(3,4-dichlorobenzyl)-4-formylpyridine (1g, 3.67 mmol) in tetrahydrofuran (10 ml) at 0° C. After 30 min., thereaction mixture was warmed to room temperature and stirred anadditional 30 min. The reaction mixture was then diluted with diethylether and washed with sodium bicarbonate solution (10 ml). The organiclayer was separated and dried over magnesium sulfate, filtered andconcentrated. The residue was subjected to flash chromatography (1:1,hexanes/ethyl acetate) to provide alcohol1(RS)-[(3,4-dichlorobenzyl)pyridin-4-yl]-2-methylpropanol (617 mg) as anoil.

Step 4

Pyridinium dichromate (6 g, 15.9 mmol) was added to a solution of1(RS)-[(3,4-dichlorobenzyl)pyridin-4-yl]-2-methylpropanol (617 mg, 1.95mmol) in N,N-dimethylformamide (35 ml) at 0° C. After 4.5 h, thereaction mixture was diluted with ethyl acetate and washed with sodiumbicarbonate solution (30 ml). The organic layer was separated and driedover magnesium sulfate, filtered and concentrated. The residue wassubjected to flash chromatography (1.5:1, hexanes/ethyl acetate) toprovide 1-[(3,4-dichlorobenzyl)pyridin-4-yl]-2-methylpropanone (432 mg)as an oil.

Step 5

Ammonium acetate (1.43 g, 18.33 mmol) followed by sodiumcyanoborohydride (130 mg, 1.86 mmol) were added to a solution of1-[(3,4-dichlorobenzyl)pyridin-4-yl]-2-methylpropanone (583 mg, 1.86mmol) in methanol 10 ml) at room temperature. After 50 h, additionalamounts of ammonium acetate (1.43 g, 18.33 mmol) and sodiumcyanoborohydride (130 mg, 1.86 mmol) were added. After 17 h, thereaction mixture was diluted with ethyl acetate and washed with sodiumbicarbonate solution (10 ml). The organic layer was separated and driedover magnesium sulfate, filtered and concentrated. The residue wasdissolved in ethyl acetate and the product extracted into 1N HClsolution. The acidic aqueous layer was made basic with sodium hydroxidesolution and the product was extracted into ethyl acetate. The organiclayer was dried over magnesium sulfate, filtered and concentrated. Theresidue was subjected to flash chromatography (90:10, methylenechloride/methanol followed by 80:20) to provide1(RS)-[(3,4-dichlorobenzyl)pyridin-4-yl]-2-methylpropylamine (390 mg) asan oil.

Step 6

3-methoxyphenyl isocyanate (37 μl, 0.28 mmol) was added to a solution ofprovide 1(RS)-[(3,4-dichlorobenzyl)pyridin-4-yl]-2-methylpropylamine (88mg, 0.28 mmol) in methylene chloride solution (2 ml) at roomtemperature. After 1 h, the reaction mixture was diluted with ethylacetate and washed with sodium bicarbonate solution (5 ml). The organiclayer was separated and dried over magnesium sulfate, filtered andconcentrated to provide1-{1(RS)-[1-(3,4-dichlorobenzyl)piperidin-4-yl]-2-methylpropyl)}-3-(3-methoxyphenyl)urea.(104 mg) as a white solid. mp 161.4-161.8° C.

Proceeding as described in Example 9, Step 6 above but substituting1(RS)-[(3,4-dichlorobenzyl)pyridin-4-yl]-2-methylpropylamine with1-(R)-[4-(3,4-dichlorobenzyl)-piperazin-1-ylmethyl]-2-methylpropylamine(prepared as described in Example 1) gave1-{1(R)-[1-(3,4-dichlorobenzyl)piperazin-1-yl]-2-methylpropyl}-3-(3-methoxyphenyl)urea.

Example 10N-{1-[1(RS)-[1-(3,4-Dichlorobenzyl)piperidin-4-ylmethyl]-2-methylpropyl}-4-methylbenzamidedihydrochloride salt

Step 1

To a suspension of 4-piperidone hydrochloride (3.52 g, 22.9 mmol) inethanol (40 ml) was added triethylamine (10.8 ml, 91.6 mmol), followedby the addition of 3,4-dichlorobenzyl bromide (5.0 g, 20.8 mmol) and thereaction mixture was stirred overnight at room temperature. The reactionmixture was concentrated in vacuo and the residue was partitionedbetween water and ethyl acetate. The ethyl acetate layer was separated,washed with brine, dried over magnesium sulfate and concentrated invacuo. Column chromatography with 25% ethyl acetate and 25%dichloromethane in hexanes gave 1-(3,4-dichlorobenzyl)-4-piperidone (4.4g) as a colorless oil.

Step 2

To a suspension of sodium hydride (0.33 g, 13.2 mmol) in dry toluene (15ml) was added triethyl phosphonoacetate (2.6 ml, 13.2 mmol) at a ratesuch that the internal reaction temperature remained below 25° C. Afterstirring at room temperature for 0.5 h, the reaction mixture wasrecooled to below 25° C. and a solution of1-(3,4-dichlorobenzyl)-4-piperidone (3.10 g, 12 mmol) in toluene (6 ml)was added dropwise. After the addition was complete, a gummy precipitateformed The mixture was heated at 60-65° C. for 10 min. and then cooledto room temperature. The mother liquor was decanted and the residue waswashed with more toluene. The combined toluene layers were filteredthrough a celite pad and concentrated in vacuo to give ethyl[1-(3,4-dichlorobenzyl)piperidin-4-ylidene]acetate (3.9 g) as an oilwhich was used in the next step without further purification.

Step 3

Ethyl [1-(3,4-dichlorobenzyl)piperidin-4-ylidene]acetate (3.9 g, 11.9mmol) dissolved in tetrahydrofuran (25 ml) and ethanol (25 ml) wassubjected to hydrogenation over platinum oxide (0.1 g) at ambienttemperature and atmospheric pressure. The reaction mixture was filteredthrough a celite pad and concentrated in vacuo to give ethyl[1-(3,4-dichlorobenzyl)piperidin-4-yl]acetate (3.91 g) as a semi-solid.

Step 4

DIBAL-H (6.9 ml, 10.35 mmol, 1.5 M in toluene) was added to a solutionof ethyl [1-(3,4-dichlorobenzyl)piperidin-4-yl]acetate (1.9 g, 5.8 mmol)in dry toluene (60 ml) at −60° C. under nitrogen atmosphere. Thereaction mixture was stirred at dry ice bath temperature for 0.5 h,quenched with saturated sodium bisulfite solution and then allowed towarm to room temperature. The aqueous layer was separated and basifiedwith 2N sodium hydroxide to pH between 8-9 and the product was extractedwith diethyl ether. The combined ether layers were washed with brine anddried over sodium sulfate. After concentration, the residue wasdissolved in dry tetrahydrofuran (30 ml) and cooled to 0° C. Isopropylmagnesium chloride (2.0 M, 5.8 ml) was added dropwise and the resultingreaction mixture was allowed to warm to room temperature. After 0.5 h,the reaction mixture was quenched with water and extracted with diethylether. The ether layer was washed with brine, dried over sodium sulfateand concentrated in vacuo. The residue was purified on silica gel columnwith 25% acetone, 25% dichloromethane in hexanes to give1(RS)-[1-(3,4-dichlorobenzyl)piperidin-4-ylmethyl]-2-methylpropanol(0.75 g) as an oil.

Step 5

Pyridinium dichromate (4.0 g, 10.63 mmol) was added to a solution of1(RS)-[1-(3,4-dichlorobenzyl)piperidin-4-ylmethyl]-2-methylpropanol (0.5g, 1.5 mmol) in dimethylformamide (25 ml) at 0° C. The resultingsolution was stirred at 0° C. until the starting material was consumedand then quenched with water, basified with 2N sodium hydroxide andextracted with ethyl acetate. The organic layer was washed with water,brine, and dried over sodium sulfate. The residue was purified on silicagel with 25% acetone, 25% dichloromethane in hexanes to give1-[1-(3,4-dichlorobenzyl)piperidin-4-yl]-3-methyl-2-butanone (0.32 g) asan oil.

Step 6

To a solution of1-[1-(3,4-dichlorobenzyl)piperidin-4-yl]-3-methyl-2-butanone (0.16 g,0.49 mmol) in methanol (1.5 ml) was added ammonium acetate (0.38 g, 4.93mmol), followed by sodium cyanoborohydride (31 mg, 0.5 mmol) and theresulting solution was stirred at room temperature. After 48 h,hydrochloric acid (conc.) was added until pH was 2 and the volatileswere removed under vacuum. The residue was dissolved in water and washedwith ethyl acetate. The aqueous layer was then basified to pH>10 andextracted with ethyl acetate. The ethyl acetate layer was washed withbrine, dried over sodium sulfate and concentrated to give1(RS)-[1-(3,4-dichlorobenzyl)piperidin-4-ylmethyl]-2-methylpropylamine(0.16 g) as an oil which was used in the next step without furtherpurification.

Step 7

p-Toluoyl chloride (0.077 ml, 0.58 mmol) was added to a solution of1(RS)-[1-(3,4-dichlorobenzyl)piperidin-4-ylmethyl]-2-methylpropylamine(0.16 g, 0.49 mmol) in dichloromethane (2 ml) and triethylamine (0.12ml, 1.63 mmol). The reaction mixture was stirred at room temperature for1.5 h and was quenched with water. The product was then extracted withdichloromethane and the organic layer was washed with brine and driedover sodium sulfate. The crude product was purified on preparative TLCwith 25% acetone, 25% dichloromethane in hexanes to give 0.21 g ofN-{1-[1(RS)-[1-(3,4-dichlorobenzyl)piperidin-4-ylmethyl]-2-methylpropyl}-4-methylbenzamideas an oil, which was then converted to its dihydrochloride salt (0.15g); m.p. 233.9-235.5° C.

Example 11N-{1-(R)-[4-(Dichlorobenzyl)piperidin-1-ylmethyl]-2-methylpropyl}-5-methylthiophene-2-carboxamidehydrochloride salt

To a solution of1-(R)-[4-(3,4-dichlorobenzyl)piperidin-1-ylmethyl]-2-methyl-propylamine(0.52 g, 1.58 mmol) [prepared as described in Example 3, Step 5), inmethylene chloride (15 ml) was added 5-methyl-2-thiophenecarboxylic acid(0.29 g, 2.05 mmol) followed by1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (0.39 g, 2.05 mmol), andthe solution was stirred under argon overnight at room temperature.After concentrating the reaction mixture, water (10 ml) and ethylacetate (25 ml) were added and the reaction mixture was stirred whileadjusting to pH 8 with dilute aqueous potassium carbonate solution. Theorganic layer was separated and the aqueous layer was extracted withethyl acetate (25 ml). The combined organic layers were dried overmagnesium sulfate, filtered and concentrated in vacuo. The crudematerial (0.86 g) was flash chromatographed on silica, eluting with 2%methanol/methylene chloride (containing 1% ammonium hydroxide) to give0.64 g product as a gum. Anhydrous HCl/ether (5 ml) was added to anether solution of the product, giving a gummy precipitate which wasfurther dissolved in methanol (10 ml) and stripped to giveN-{1-(R)-[4-(dichlorobenzyl)piperidin-1-ylmethyl]-2-methylpropyl}-5-methylthiophene-2-carboxamidehydrochloride salt (0.72 g) as a light yellow foam.

Example 12N-{1-(R)-[4-(Dichlorobenzyl)piperidin-1-ylmethyl]-2-methylpropyl}-4-(2-aminoethyl)benzamidedihydrochloride salt

Step 1

A solution of 4-bromophenethylamine (10 g, 50 mmol),di-tert-butyldicarbonate (21.82 g, 100 mmol), triethylamine (13.9 ml,100 mmol), and anhydrous methanol (350 ml) was refluxed for 2 h. Thereaction mixture was concentrated in vacuo and the residue was stirredwith water, filtered, washed with water and air dried to giveN-(tert-butoxycarbonyl)-4-bromophenethylamine (15 g).

Step 2

To a 0° C. solution of N-(tert-butoxycarbonyl)-4-bromophenethylamine(12.82 g, 42.6 mmol) in anhydrous ether (200 ml) under argon was addeddropwise n-butyllithium (34 ml, 85.2 mmol, 2.5 M in hexane). Theslightly yellow solution turned milky white and was stirred 15 min., at0° followed by one hour at room temperature. The resulting mixture wascooled to −78° C. in a dry ice-acetone bath. Dry carbon dioxide wasbubbled through the stirring reaction mixture for 30 min., and then thereaction mixture was allow to slowly warm to room temperature over 30min. Water (100 ml) was added, the pH adjusted to 8 with dilute aqueouspotassium carbonate solution, and the aqueous layer was separated andextracted with ethyl acetate. The aqueous layer was then cooled to 0° C.and acidified to pH 3 with 3 N aqueous hydrochloric acid. The resultingwhite precipitate was filtered, washed with water and air dried toprovide 4-[2-(N-tert-butoxycarbonylamino)ethyl]benzoic acid (7.8 g).

Step 3

To a room temperature solution of1-(R)-[4-(3,4-dichlorobenzyl)piperidin-1-yl-methyl]-2-methylpropylamine(1 g, 3.04 mmol) (prepared as described in Example 3, Step 5) inmethylene chloride (30 ml) was added4-[2-(N-tert-butoxycarbonylamino)-ethyl]benzoic acid (1 g, 3.8 mmol)followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (0.73 g, 3.8mmol) and the solution was stirred under argon overnight at roomtemperature. After concentrating the reaction mixture, water (25 ml) andethyl acetate (60 ml) were added and the reaction mixture was stirredwhile adjusting the pH to 8 with dilute aqueous potassium carbonatesolution. The organic layer was separated and the aqueous layer wasextracted with ethyl acetate (50 ml). The combined organic layers weredried over magnesium sulfate and concentrated. The resulting crudeproduct was flash chromatographed on silica, eluting with 2%-4%methanol/methylene chloride containing 1% ammonium hydroxide to giveN-{1-[1(R)-[1-(3,4-dichlorobenzyl)-piperidin-4-ylmethyl]-2-methylpropyl}-4-[2-(N-tert-butoxycarbonylamino)ethyl]-benzamideas a white foam.

Step 4

To a room temperature solution of giveN-{1-[1(R)-[1-(3,4-dichlorobenzyl)-piperidin-4-ylmethyl]-2-methylpropyl}-4-[2-(N-tert-butoxycarbonylamino)ethyl]-benzamide(1.34 g, 2.32 mmol) in methylene chloride (30 ml) was addedtrifluoroacetic acid (30 ml). After 3 h, the reaction mixture wasconcentrated in vacuo and the residue was stirred with ethyl acetate(100 ml) and water (50 ml) while adjusting the pH to 8 with 15% aqueoussodium hydroxide solution. The organic layer was separated and theaqueous layer was extracted twice with ethyl acetate. The combinedorganic portions were dried with magnesium sulfate and concentrated. Thecrude was flash chromatographed on silica, eluting with 3%methanol/methylene chloride (containing 1% ammonium hydroxide). The freebase product was dissolved in anhydrous ether and 1N anhydrous HCl/etherwas added to giveN-{1-(R)-[4-(dichlorobenzyl)piperidin-1-yl-methyl]-2-methylpropyl}-4-(2-aminoethyl)benzamideas the hydrochloride salt, mp 190.5-261.6° C.

Example 131-{1-(R)-[4-(3,4-Dichlorobenzyl)piperidin-1-ylmethyl]-2-methylpropyl}-3-(3-methoxyphenyl)urea

To a room temperature solution of1-(R)-[4-(3,4-dichlorobenzyl)piperidin-1-ylmethyl]-2-methylpropylamine(0.349 g, 1.06 mmol) (prepared as in Example 3, steps 4 and 5, but usingD-Boc-Valine in place of L-Boc-Valine) in methylene chloride (50 ml) wasadded 3-methoxyphenylisocyanate (0.17 ml, 1.27 mmol) and the reactionmixture was stirred at room temperature under argon for 2 h. Thereaction mixture was concentrated in vacuo and the crude product wasflash chromatographed on silica, eluting with 1-3% methanol/methylenechloride (containing 1% ammonium hydroxide). The product was dissolvedin anhydrous ether and 1N anhydrous HCl/ether was added to precipitate1-{1-(R)-[4-(3,4-dichlorobenzyl)piperidin-1-ylmethyl]-2-methylpropyl}-3-(3-methoxyphenyl)-ureaas the hydrochloride salt (0.29 g), mp 107-112° C.

Proceeding as described in Example 13 above, but substituting3-methoxyphenylisocyanate with 3,4,5-trimethoxyphenylisocyanate gave1-{1-(R)-[4-(3,4-dichlorobenzyl)-piperidin-1-ylmethyl]-2-methylpropyl}-3-(3,4,5-trimethoxyphenyl)urea.

Proceeding as described in Example 13 above, but substituting3-methoxyphenylisocyanate with 3,4,5-trimethoxyphenylisocyanate and1-(R)-[4-(3,4-dichlorobenzyl)-piperidin-1-ylmethyl]-2-methylpropylaminewith1-(R)-[4-(3,4-dichlorobenzyl)-piperidin-1-ylmethyl]-2,2-dimethylpropylaminegave1-{1-(R)-[4-(3,4-dichlorobenzyl)-piperidin-1-ylmethyl]-2,2-dimethylpropyl}-3-(3,4,5-trimethoxyphenyl)urea.

Proceeding as described in Example 13 above, but substituting3-methoxyphenylisocyanate with 3-nitrophenylisocynate gave1-{1-(R)-[4-(3,4-dichlorobenzyl)-piperidin-1-ylmethyl]-2-methylpropyl}-3-(3-nitrophenyl)ureawhich was then converted to the corresponding1-{1-(R)-[4-(3,4-dichlorobenzyl)piperidin-1-ylmethyl]-2-methylpropyl}-3-(3-aminophenyl)ureaunder catalytic hydrogenation conditions using PtO₂ catalyst, followedby reaction with methylsulfonyl chloride to give1-{1-(R)-[4-(3,4-dichlorobenzyl)-piperidin-1-ylmethyl]-2-methylpropyl}-3-(3-methylsulfonylaminophenyl)urea.

Example 14 Formulation Examples

The following are representative pharmaceutical formulations containinga compound of Formula (I).

Tablet Formulation

The following ingredients are mixed intimately and pressed into singlescored tablets.

Quantity per Ingredient tablet, mg compound of this invention 400cornstarch 50 croscarmellose sodium 25 lactose 120 magnesium stearate 5

Capsule Formulation

The following ingredients are mixed intimately and loaded into ahard-shell gelatin capsule.

Quantity per Ingredient capsule, mg compound of this invention 200lactose, spray-dried 148 magnesium stearate 2

Suspension Formulation

The following ingredients are mixed to form a suspension for oraladministration.

Ingredient Amount compound of this invention 1.0 g fumaric acid 0.5 gsodium chloride 2.0 g methyl paraben 0.15 g propyl paraben 0.05 ggranulated sugar 25.5 g sorbitol (70% solution) 12.85 g Veegum K(Vanderbilt Co.) 1.0 g flavoring 0.035 ml colorings 0.5 mg distilledwater q.s. to 100 ml

Injectable Formulation

The following ingredients are mixed to form an injectable formulation.

Ingredient Amount compound of this invention 0.2 g sodium acetate buffersolution, 0.4 M 2.0 ml HCl (1N) or NaOH (1N) q.s. to suitable pH water(distilled, sterile) q.s. to 20 ml

Example 15 CCR-3 Receptor Binding Assay—In Vitro

The CCR-3 antagonistic activity of the compounds of the invention wasdetermined by their ability to inhibit the binding of ¹²⁵I eotaxin toCCR-3 L1.2 transfectant cells ((see Ponath, P. D. et al., J. Exp. Med.,Vol. 183, 2437-2448, (1996)).

The assay was performed in Costar 96-well polypropylene round bottomplates. Test compounds were dissolved in DMSO and then diluted withbinding buffer (50 mM HEPES, 1 mM CaCl₂, 5 mM MgCl₂, 0.5% bovine serumalbumin (BSA), 0.02% sodium azide, pH 7.24) such that the final DMSOconcentration was 2%. 25 μl of the test solution or only buffer withDMSO (control samples) was added to each well, followed by the additionof 25μl of ¹²⁵I-eotaxin (100 pmol) (NEX314, New England Nuclear, Boston,Mass.) and 1.5×10⁵ of the CCR-3 L1.2 transfected cells in 25 μl bindingbuffer. The final reaction volume was 75 μl.

After incubating the reaction mixture for 1 h at room temperature, thereaction was terminated by filtering the reaction mixture throughpolyethylenimine treated Packard Unifilter GF/C filter plate (Packard,Chicago, Ill.). The filters were washed four times with ice cold washbuffer containing 10 mm HEPES and 0.5M sodium chloride (pH 7.2) anddried at 65° C. for approximately 10 min. 25 μl/well of Microscint-20™scintillation fluid (Packard) was added and the radioactivity retainedon the filters was determined by using the Packard TopCount™.

Compounds of this invention were active in this assay.

The IC₅₀ value (concentration of test compound required to reduce¹²⁵I-eotaxin binding to the CCR-3 L 1.2 transfected cells by 50%) forsome of the compounds of the invention was:

Cpd # IC₅₀, μM Cpd # IC₅₀, μM 7 0.415 88 1.47 8 0.24 89 1.68 19 0.945 911.89 20 0.952 93 3.37 23 1.33 99 2.36 24 1.37 100 2.47 25 1.46 107 1.1459 0.95 109 2.84 61 1.76 110 3.05 78 5.03 117 1.33 84 0.69 118 1.5 861.16 121 3.52

Example 16 Inhibition of Eotaxin Mediated Chemotaxis of CCR-3 L1.2Transfectant Cells—In Vitro Assay

The CCR-3 antagonistic activity of the compounds of this invention wasdetermined by measuring the inhibition of eotaxin mediated chemotaxis ofthe CCR-3 L1.2 transfectant cells, using a slight modification of themethod described in Ponath, P. D. et al., J. Clin. Invest. 97: 604-612(1996). The assay was performed in a 24-well chemotaxis plate (CostarCorp., Cambridge Mass.). CCR-3 L1.2 transfectant cells were grown inculture medium containing RPMI 1640, 10% Hyclone™ fetal calf serum, 55mM 2-mercaptoethanol and Geneticin 418 (0.8 mg/ml). 18-24 hours beforethe assay, the transfected cells were treated with n-butyric acid at afinal concentration of 5 mM/1×10⁶ cells/ml, isolated and resuspended at1×10⁷ cells/ml in assay medium containing equal parts of RPMI 1640 andMedium 199 (M 199) with 0.5% bovine serum albumin.

Human eotaxin suspended in phosphate buffered saline at 1 mg/ml wasadded to bottom chamber in a final concentration of 100 nm. Transwellculture inserts (Costar Corp., Cambridge Mass.) having 3 micron poresize were inserted into each well and L1.2 cells (1×10⁶) were added tothe top chamber in a final volume of 100 μl. Test compounds in DMSO wereadded both to the top and bottom chambers such that the final DMSOvolume was 0.5%. The assay was performed against two sets of controls.The positive control contained cells with no test compound in the topchamber and only eotaxin in the lower chamber. The negative controlcontained cells with no test compound in the top chamber and neithereotaxin nor test compound in lower chamber. The plate was incubated at37° C. After 4 h, the inserts were removed from the chambers and thecells that had migrated to the bottom chamber were counted by pipettingout 500 μl of the cell suspension from the lower chamber to 1.2 mlCluster tubes (Costar) and counting them on a FACS for 30 sec.

Compounds of this invention were active in this assay.

The IC₅₀ value (concentration of test compound required to reduceeotaxin mediated chemotaxis of CCR-3 L 1.2 transfected cells by 50%) forsome of the compounds of the invention was:

CPD # IC₅₀ μM CPD # IC₅₀ μM 57 0.24 84 0.46 59 0.21 93 0.06

Example 17 Inhibition of Eotaxin Mediated Chemotaxis of HumanEosinophils—In Vitro Assay

The ability of compounds of the invention to inhibit eotaxin mediatedchemotaxis of human eosinophils was assessed using a slight modificationof procedure described in Carr, M. W. et al., Proc. Natl. Acad. Sci.USA, 91: 3652-3656 (1994). Experiments were performed using 24 wellchemotaxis plates (Costar Corp., Cambridge Mass.). Eosinophils wereisolated from blood using the procedure described in PCT Application,Publication No. WO 96/22371. The endothelial cells used were theendothelial cell line ECV 304 obtained from European Collection ofAnimal Cell Cultures (Porton Down, Salisbury, U.K.). Endothelial cellswere cultured on 6.5 mm diameter Biocoat® Transwell tissue cultureinserts (Costar Corp., Cambridge Mass.) with a 3.0 μM pore size. Culturemedia for ECV 304 cells consisted of M199, 10% Fetal Calf Serum,L-glutamine and antibiotics. Assay media consisted of equal parts RPMI1640 and M199, with 0.5% BSA. 24 h before the assay 2×10⁵ ECV 304 cellswere plated on each insert of the 24-well chemotaxis plate and incubatedat 37° C. 20 nM of eotaxin diluted in assay medium was added to thebottom chamber. The final volume in bottom chamber was 600 μl. Theendothelial coated tissue culture inserts were inserted into each well.10⁶ eosinophil cells suspended in 100 μl assay buffer were added to thetop chamber. Test compounds dissolved in DMSO were added to both top andbottom chambers such that the final DMSO volume in each well was 0.5%.The assay was performed against two sets of controls. The positivecontrol contained cells in the top chamber and eotaxin in the lowerchamber. The negative control contained cells in the top chamber andonly assay buffer in the lower chamber. The plates were incubated at 37°C. in 5% CO₂/95% air for 1-1.5 h.

The cells that had migrated to the bottom chamber were counted usingflow cytometry. 500 μl of the cell suspension from the lower chamber wasplaced in a tube, and relative cell counts were obtained by acquiringevents for a set time period of 30 seconds.

Compounds of this invention were active in this assay.

Example 18 Inhibition of Eosinophil Influx into the Lungs of OvalbuminSensitized balb/c Mice by CCR-3 Antagonist—In Vivo Assay

The ability of the compounds of the invention to inhibit leukocyteinfiltration into the lungs was determined by measuring the inhibitionof eosinophil accumulation into the bronchioalveolar lavage (BAL) fluidof Ovalbumin (OA)-sensitized balb/c mice after antigen challenge byaerosol. Briefly, male balb/c mice weighing 20-25 g were sensitized withOA (10 μg in 0.2 ml aluminum hydroxide solution) intraperitoneally ondays 1 and 14. After a week, the mice were divided into ten groups. Testcompound or only vehicle (control group) or anti-eotaxin antibody(positive control group) was administered. After 1 h, the mice wereplaced in a Plexiglass box and exposed to OA aerosol generated by aPARISTAR™ nebulizer (PARI, Richmond, Va.) for 20 min. Mice which had notbeen sensitized or challenged were included as negative control. After24 or 72 h, the mice were anesthetized (urethane, approx. 1 g/kg, i.p.),a tracheal cannula (PE 60 tubing) was inserted and the lungs werelavaged four times with 0.3 ml PBS. The BAL fluid was transferred intoplastic tubes and kept on ice. Total leukocytes in a 20 μl aliquot ofthe BAL fluid was determined by Coulter Counter™ (Coulter, Miami, Fla.).Differential leukocyte counts were made on Cytospin™ preparations whichhad been stained with a modified Wright's stain (Diff-Quick™) by lightmicroscopy using standard morphological criteria.

Compounds of this invention were active in this assay.

The foregoing invention has been described in some detail by way ofillustration and example, for purposes of clarity and understanding. Itwill be obvious to one of skill in the art that changes andmodifications may be practiced within the scope of the appended claims.Therefore, it is to be understood that the above description is intendedto be illustrative and not restrictive. The scope of the inventionshould, therefore, be determined not with reference to the abovedescription, but should instead be determined with reference to thefollowing appended claims, along with the full scope of equivalents towhich such claims are entitled.

All patents, patent applications and publications cited in thisapplication are hereby incorporated by reference in their entirety forall purposes to the same extent as if each individual patent, patentapplication or publication were so individually denoted.

1. A compound selected from compounds of Formula (I):

wherein: R¹ and R² are, independently of each other, hydrogen or alkyl;n is an integer from 0 to 2; m is an integer from 0 to 3; Ar and Ar¹are, independently of each other, aryl or heteroaryl, wherein at leastone of Ar and Ar¹ is heteroaryl; F is alkylene, alkenylene or a bond;each R is independently hydrogen or alkyl, or R together with either R³or R⁴ and the atoms to which they are attached form a carbocycle or aheterocycle; R³ and R⁴ are, independently of each other, selected from:(i) hydrogen, alkyl, alkenyl, haloalkyl, cycloalkyl, cycloalkylalkyl,heteroaryl, heteroaralkyl, heterocyclyl, heterocyclylalkyl, heteroalkyl,cyano or -(alkylene)-C(O)—Z where Z is alkyl, haloalkyl, alkoxy,haloalkyloxy, hydroxy, amino, mono- or disubstituted amino, aryl,aralkyl, aryloxy, aralkyloxy, heteroaryl, heteroaryloxy orheteroaralkyloxy, provided that both R³ and R⁴ are not hydrogen; or (ii)R³ and R⁴ together with the carbon atom to which they are attached forma carbocycle or a heterocycle; E is —SO₂N(R⁵)—, —N(R⁶)SO₂N(R⁵)—, or—N(R⁶)SO₂— wherein: R⁵ is hydrogen, alkyl, acyl, haloalkyl, cycloalkyl,cycloalkylalkyl, aryl, aralkyl, aralkenyl, heteroaryl, heteroaralkyl,heterocyclylalkyl, heteroalkyl, or -(alkylene)-C(O)—Z where Z is alkyl,haloalkyl, alkoxy, haloalkyloxy, hydroxy, amino, mono- or disubstitutedamino, aryl, aralkyl, aryloxy, aralkyloxy, heteroaryl, heteroaryloxy orheteroaralkyloxy; R⁶ is hydrogen, alkyl, acyl, haloalkyl, cycloalkyl,cycloalkylalkyl, aryl, aralkyl, aralkenyl, heteroaryl, heteroaralkyl,heterocyclylalkyl, heteroalkyl, or -(alkylene)-C(O)—Z where Z is alkyl,haloalkyl, alkoxy, haloalkyloxy, hydroxy, amino, mono- or disubstitutedamino, aryl, aralkyl, aryloxy, aralkyloxy, heteroaryl, heteroaryloxy orheteroaralkyloxy, provided that when E is —SO₂N(R⁵)— or —N(R⁶)SO₂N(R⁵)—,then m>0; Q is —R⁷—W—R⁸— wherein: R⁷ is an alkylene chain of between 1-6carbon atoms inclusive; R⁸ is a bond or an alkylene chain of between 1-4carbon atoms inclusive; W is a bond or a group selected from —C(O)—,—NR⁹—, —O—, —S(O)₀₋₂—, —N(R⁹)C(O)—, —N(R⁹)SO₂—, —SO₂N(R⁹)—,—N(R⁹)C(O)N(R⁹)—, —N(R⁹)SO₂N(R⁹)— or —N(R⁹)C(S)N(R⁹)— wherein: R⁹ ishydrogen, alkyl, acyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl,aralkyl, aralkenyl, heteroaryl, heteroaralkyl, heterocycloalkyl,heteroalkyl, or -(alkylene)-C(O)—Z where Z is alkyl, haloalkyl, alkoxy,haloalkyloxy, hydroxy, amino, mono- or disubstituted amino, aryl,aralkyl, aryloxy, aralkyloxy, heteroaryl, heteroaryloxy orheteroaralkyloxy; and individual isomers, mixtures of isomers andpharmaceutically acceptable salts thereof.
 2. The compound of claim 1,wherein: n and m are 1; F is a bond; Q is an alkylene chain of between 1to 6 carbon atoms inclusive; and E is —SO₂N(R⁵)—.
 3. The compound ofclaim 2, wherein R⁴ is alkyl or heteroalkyl and R⁵ and R⁶ are hydrogen.4. The compound of claim 3, wherein R⁴ is 1-methylethyl,1,1-dimethylethyl, 2-methylpropyl, 3-hydroxypropyl, 1-hydroxyethyl or2-hydroxyethyl.
 5. A pharmaceutical composition comprising atherapeutically effective amount of a compound of claim 1 together witha pharmaceutically acceptable excipient.
 6. A method of treatinginflammatory or allergic disease in a mammal, which method comprisesadministering to said mammal a therapeutically effective amount of acompound of Formula (I):

wherein: R¹ and R² are, independently of each other, hydrogen or alkyl;n is an integer from 0 to 2; m is an integer from 0 to 3; Ar and Ar¹are, independently of each other, aryl or heteroaryl, wherein at leastone of Ar and Ar¹ is heteroaryl; F is alkylene, alkenylene or a bond;each R is independently hydrogen or alkyl, or R together with either R³or R⁴ and the atoms to which they are attached form a carbocycle or aheterocycle; R³ and R⁴ are, independently of each other, selected from:(i) hydrogen, alkyl, alkenyl, haloalkyl, cycloalkyl, cycloalkylalkyl,heteroaryl, heteroaralkyl, heterocyclyl, heterocyclylalkyl, heteroalkyl,cyano or -(alkylene)-C(O)—Z where Z is alkyl, haloalkyl, alkoxy,haloalkyloxy, hydroxy, amino, mono- or disubstituted amino, aryl,aralkyl, aryloxy, aralkyloxy, heteroaryl, heteroaryloxy orheteroaralkyloxy, provided that both R³ and R⁴ are not hydrogen; or (ii)R³ and R⁴ together with the carbon atom to which they are attached forma carbocycle or a heterocycle; E is —SO₂N(R⁵)—, —N(R⁶)SO₂N(R⁵)—, or—N(R⁶)SO₂— wherein: R⁵ is hydrogen, alkyl, acyl, haloalkyl, cycloalkyl,cycloalkylalkyl, aryl, aralkyl, aralkenyl, heteroaryl, heteroaralkyl,heterocyclylalkyl, heteroalkyl, or -(alkylene)-C(O)—Z where Z is alkyl,haloalkyl, alkoxy, haloalkyloxy, hydroxy, amino, mono- or disubstitutedamino, aryl, aralkyl, aryloxy, aralkyloxy, heteroaryl, heteroaryloxy orheteroaralkyloxy; R⁶ is hydrogen, alkyl, acyl, haloalkyl, cycloalkyl,cycloalkylalkyl, aryl, aralkyl, aralkenyl, heteroaryl, heteroaralkyl,heterocyclylalkyl, heteroalkyl, or -(alkylene)-C(O)—Z where Z is alkyl,haloalkyl, alkoxy, haloalkyloxy, hydroxy, amino, mono- or disubstitutedamino, aryl, aralkyl, aryloxy, aralkyloxy, heteroaryl, heteroaryloxy orheteroaralkyloxy, provided that when E is —SO₂N(R⁵)— or —N(R⁶)SO₂N(R⁵)—,then m>0; Q is —R⁷—W—R⁸— wherein: R⁷ is an alkylene chain of between 1-6carbon atoms inclusive; R⁸ is a bond or an alkylene chain of between 1-4carbon atoms inclusive; W is a bond or a group selected from —C(O)—,—NR⁹—, —O—, —S(O)₀₋₂—, —N(R⁹)C(O)—, —N(R⁹)SO₂—, —SO₂N(R⁹)—,—N(R⁹)C(O)N(R⁹)—, —N(R⁹)SO₂N(R⁹)— or —N(R⁹)C(S)N(R⁹)— wherein: R⁹ ishydrogen, alkyl, acyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl,aralkyl, aralkenyl, heteroaryl, heteroaralkyl, heterocycloalkyl,heteroalkyl, or -(alkylene)-C(O)—Z where Z is alkyl, haloalkyl, alkoxy,haloalkyloxy, hydroxy, amino, mono- or disubstituted amino, aryl,aralkyl, aryloxy, aralkyloxy, heteroaryl, heteroaryloxy orheteroaralkyloxy; and individual isomers, mixtures of isomers andpharmaceutically acceptable salts thereof.
 7. The method of claim 6,wherein said inflammatory or allergic disease is selected from asthma,allergic rhinitis, hypersensitivity lung disease, hypersensitivitypneumonitis, eosinophilic pneumonia, inflammatory bowel disease,psoriasis, dermatitis and eczema.